17beta-amino and hydroxylamino-11beta-arylsteroids and their derivatives having agonist or antagonist hormonal properties

ABSTRACT

The invention is directed to a novel class of steroids which exhibit potent antiprogestational activity.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to a novel class of 17β-amino andhydroxylamino steroids which are believed to bind to the progestinreceptor and which exhibit potent antiprogestational activity, steroidintermediates which are useful for preparing same and methods for thepreparation of steroid intermediates. Such compounds are useful fortreatment of fibroids, endometriosis, and certain tumors, in causingcervical ripening prior to delivery, in hormone replacement therapy andin control of fertility and reproduction.

[0003] 2. Discussion of the Background

[0004] Progesterone plays a major role in reproductive health andfunctioning. Its effects on, for example, the uterus, breast, cervix andhypothalamic-pituitary unit are well established. It also hasextra-reproductive activities that are less well studied, such aseffects on the brain, the immune system, the vascular endothelial systemand on lipid metabolism. Given this wide array of effects, it isapparent that compounds which mimic some of the effects of progesterone(agonists), antagonize these effects (antagonists) or exhibit mixedeffects (partial agonists or mixed agonist/antagonist) can be useful intreating a variety of disease states and conditions.

[0005] Steroid hormones exert their effects, in-part, by binding tointracellular receptors. Compounds that bind to the appropriatereceptors and are antagonists or partial agonists of the estrogenic andandrogenic hormones have long been known, but it was not until around1982 that the discovery of compounds that bind to the progesteronereceptor and antagonize the effects of progesterone was announced. Sincethen, a number of such compounds have been reported in the scientificand patent literature and their effects in vitro, in animals and inhumans have been studied. Although compounds such as estrogens andcertain enzyme inhibitors can prevent the physiological effects ofendogenous progesterone, in this discussion “antiprogestin” is confinedto those compounds that bind to the progestin receptor.

[0006] Information indicating that antiprogestins would be effective ina number of medical conditions is now available. This information hasbeen summarized in a report from the Institute of Medicine (Donaldson,Molly S.; Dorflinger, L.; Brown, Sarah S.; Benet, Leslie Z., Editors,Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins,Committee on Antiprogestins: Assessing the Science, Institute ofMedicine, National Academy Press, 1993). In view of the pivotal rolethat progesterone plays in reproduction, it is not surprising thatantiprogestins could play a part in fertility control, includingcontraception (long-term and emergency or post-coital), menses inductionand medical termination of pregnancy, but there are many other potentialuses that have been supported by small clinical or preclinical studies.Among these are the following:

[0007] 1. Labor and delivery—antiprogestins may be used for cervicalripening prior to labor induction such as at term or when labor must beinduced due to fetal death. They may also be used to help induce laborin term or post-term pregnancies.

[0008] 2. Treatment of uterine leiomyomas (fibroids)—these non-malignanttumors may affect up to 20% of women over 30 years old and are one ofthe most common reasons for surgery in women during their reproductiveyears. Hysterectomy, the common treatment for persistent symptoms, ofcourse results in sterility.

[0009] 3. Treatment of endometriosis—this common (5 to 15% incidence,much larger in infertile women) and often painful condition is nowtreated with drugs such as danazol or gonadotrophin-releasing hormoneanalogs that have significant side-effects, or must be dealt withsurgically.

[0010] 4. Hormone replacement therapy, where they may be given tointerupt or curtail the activity of progestins.

[0011] 5. Cancers, particularly breast cancers—the presence of progestinreceptors in many breast cancers has suggested the use of antiprogestinsin treating metatstatic cancer or in prevention of recurrence or initialdevelopment of cancer.

[0012] 6. Other tumors such as meningiomas—these brain membrane tumors,although non-malignant, result in death of the patient and nonsurgicaltreatments are lacking.

[0013] 7. Male contraception—antiprogestins can interfere with spermviability, although whether this is an antiprogestational effect or notis controversial, as it may relate to the antiglucocorticoid activity ofsuch compounds.

[0014] 8. Antiestrogenic effects—at least some antiprogestins oppose theaction of estrogens in certain tests, but apparently through a mechanismthat does not involve classical hormone receptors. This opens a varietyof possibilities for their medical use.

[0015] 9. Antiglucocorticoid effects—this is a common side-effect ofantiprogestins, which can be useful in some instances, such as thetreatment of Cushing's syndrome, and could play a role in immunedisorders, for example. In other instances it is desirable to minimizesuch effects.

[0016] The effects and uses of progesterone agonists have been welldocumented. In addition, it has been recently shown that certaincompounds structurally related to the known antiprogestins have strongagonist activity in certain biological systems (e.g., the classicalprogestin effects in the estrogen-primed immature rabbit uterus; cf. C.E. Cook et al., Life Sciences, 52, 155-162 (1993)). Such compounds arepartial agonists in human cell-derived receptor systems, where they bindto a site distinct from both the progestin and antiprogestin sites(Wagner et al., Proc. Natl. Acad. Sci., 93, 8739-8744 (1996)). Thus thegeneral class of antiprogestins can have subclasses, which may vary intheir clinical profiles.

[0017] Generally antiprogestational activity has been associated withthe presence of an 11β-aryl substituent on the steroid nucleus, togetherwith a Δ^(4,9)-3-ketone or Δ⁴-3-ketone moiety. However, it has beenshown that substituents on the D-ring of the steroid can have a markedinfluence on the biological profile of these compounds (see above). Theearliest antiprogestins were substituted with a 17β-hydroxyl group andvarious 17α-substituents. (See for example, Teutsch, Jean G.;Costerousse, Germain; Philibert, Daniel, and Deraedt, Roger. Novelsteroids. U.S. Pat. No. 4,386,085. 1983; Philibert, Daniel; Teutsch,Jean G.; Costerousse, Germain, and Deraedt, Roger.3-Keto-19-nor-Δ-4,9-steroids. U.S. Pat. No. 4,477,445. 1983; Teutsch,Jean G.; Pantin, Germain; Costerousse, Saint-Maurice; Daniel Philibert;La Varenne Saint Hilaire; Roger Deraedt, inventors. Steroid derivatives.Roussel Uclaf, assignee. U.S. Pat. No. 4,447,424. 1984; Cook, C. Edgar;Tallent, C. Ray; Reel, Jerry R., and Wani, Mansukh C.17α-(Substituted-methyl)-17β-hydroxy/esterified hydroxy steroids andpharmaceutical compositions containing them. U.S. Pat. Nos. 4,774,236(1988) and 4,861,763 (1989)). Then it was discovered that a 17β-acetyl,17α-acyloxy group could also generate antiprogestational effects (Cook,C. Edgar; Lee, Y.-W.; Reel, Jerry R.; Wani, Mansukh C., Rector, Douglas.11β-Substituted Progesterone Analogs. U.S. Pat. Nos. 4,954,490 (1990)and 5,073,548 (1991)), and various permutations of these findings havebeen made as well. However, introduction of a 16α-ethyl group or ahydrogen substituent at the 17α-position in the 17β-acyl series ofcompounds leads to agonist or partial agonist activity (C. E. Cook etal., Life Sciences, 52, 155-162 (1993)). Thus changes in the D-ring ofthe steroid result in a wide variety of effects on the biologicalactivity. Accordingly there remains a need for antiprogestin compoundswhich exhibit higher specificity.

[0018] It can be seen that the 17β-position of current antiprogestinshas been characterized by substitution with a carbon or an oxygen atom.No reports have been made of the effect of nitrogen substituents such asamines, amine amides, and hydroxylamines in the 17β-position of 11β-arylsteroids on their hormonal or antihormonal activity. Until the currentinvention there existed no methods for their synthesis. Very few17β-amino and hydroxylamino steroids and none with 11β-substitution havebeen reported in either the general chemical literature or in patents.Indeed, one of the few reports of this type of 17β-substitution (P.Kaspar and H. Witzel, J. Steroid. Biochem., 23: 259 (1985)) shows thatthis type of substitution in the estrogen field leads to compounds thatare one or more orders of magnitude less potent (as measured by receptorbinding or standard in vivo tests for estrogenicity) than thecorresponding 17β-hydroxy compounds. One novel feature of the presentinvention is the finding that 17β-nitrogen substituents in 11β-arylsteroids result in compounds with good binding to the progestin receptorand with surprisingly potent antiprogestational activity, or with potentantiprogestational activity accompanied by some progestational activity.Another novel feature of the present invention is the finding that17β-nitrogen substituents in 11β-aryl steroids result in compoundshaving unusual antiestrogenic activity.

[0019] In addition, this invention provides a group of novel 17,17-spirocyclic tetrahydropyrrole steroids. Although a very few 17,17-spirocyclic tetrahydropyrrole steroids are known (cf. Keana, John F. W.;Tamura, Toshinari; McMillen, Debra A., and Jost, Patricia C. Synthesisand characterization of a novel cholesterol nitroxide spin label.Application to the molecular organization of human high-densitylipoprotein. J. Am. Chem. Soc. 1981; 103(16):4904-4912), these have beenused to develop spin labels and not for their biological properties. Nosuch compounds with 11β-aryl substituents have been reported. Again, anovel feature of the present invention is the finding that thesecompounds surprisingly bind well to the progestin receptor and exhibitantiprogestational activity.

[0020] It is therefore the purpose of the present invention to providenovel and potent progestin antagonists (antiprogestins) and mixed orpartial progestin agonists, to provide methods for their medical use inmammals, including humans, and to provide methods for their synthesis.

[0021] In spite of the clinical promise of antiprogestins, as of May 1,1998, there were no antiprogestin drugs marketed in the United States ormany other countries. Only one antiprogestin drug is approved andavailable for clinical use anywhere in the world and that drug,mifepristone, is mainly used for medical termination of pregnancy. Anumber of factors are the cause of this situation, but certainly a needexists for new antiprogestational drugs that can be used for theconditions described above.

[0022] It is therefore the purpose of the present invention to providenovel and potent progestin antagonists (antiprogestins) and mixed orpartial progestin agonists, and to provide methods for their medical usein mammals, including humans.

SUMMARY OF THE INVENTION

[0023] This invention provides a group of novel 17β-amino and hydroxyamino steroids, which are characterized by 11β-substitution,particularly 11β-aryl substitution.

[0024] According to one embodiment of the present invention is ahormonal or antihormonal steroid compound of structure I,

[0025] wherein

[0026] R¹ is (R² R³ N(O)_(r)), where r is 0 or 1 and R² and R³ are eachindependently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, any of which may be optionally substituted; or

[0027] R¹ is

[0028] where q is 0 or 1, Y is —(CH₂)_(m)— where m is an integer of 0 to5, or Y is —(CH₂)_(m)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p isan integer of 0 to 2, and Z is a heteroatom (optionally substituted) andwhere the CH₂ groups may be optionally substituted; or

[0029] R¹ is N-imidazolyl,- N-pyrrolyl-, H, halo-, HO—, CF₃SO₂O—, C₁₋₆alkyl-O—, C₁₋₆ alkyl-S—, C₁₋₆ alkyl-S(O)—, C₁₋₆ alkyl-S(O₂)—, C₁₋₆alkyl-CO—, C₁₋₆ alkyl-CH(OH)—, NC—, HCC—, C₆H₅CC—, 2′-furyl, 3′-furyl,2′-thiophenyl, 3′-thiophenyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl,2′-thiazolyl, 2′-N-methylimidazolyl, 5′-pyrimidinyl, C₆H₅—, H₂C═CH—,C₁₋₆ alkyl, or MeC(═CH₂)—;

[0030] R¹² is H or halo; or

[0031] R¹ and R¹² combine to form a ring

[0032] where W is CH₂, CH, NH, N, O, or S, and R⁴ is H or C₁₋₆ alkyl;

[0033] X is O or NOR⁵, where R⁵ is H or C₁₋₆ alkyl, C₃₋₈ cycloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₂ aryl, or heteroaryl, any of which maybe optionally substituted; or

[0034] X is (H, H), (H, OH), (H, OSi(C₁₋₆ alkyl)₃), or (H, OCOR⁵), whereR⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₂aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl, any of which may be optionallysubstituted; or

[0035] where Y is —(CH₂)_(m)— where m is an integer of 0 to 3, or Y is—(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is an integerof 0 to 2 and Z is a heteroatom (optionally substituted) or Z is acarbon atom substituted with one or two C₁₋₆ alkyl groups;

[0036] R⁶ is H, C₁₋₆ alkyl or halogen;

[0037] R⁷ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl, any of which may be optionallysubstituted, CN, COOR¹⁰ or CONHR¹⁰, where R¹⁰ is H, C₁₋₁₈ alkyl, C₂₋₁₈alkenyl, C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl,aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl orheteroaralkynyl, any of which may be optionally substituted;

[0038] s is 0 or 1;

[0039] R⁸ and R⁹ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl, R¹⁰CO, OR¹¹, any of which may be optionally substituted,

[0040] where R¹⁰ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,heteroaralkyl, heteroaralkenyl or heteroaralkynyl any of which may beoptionally substituted, and

[0041] where R¹¹ is H, C₁₋₆ alkyl, Si(C₁₋₆ alkyl)₃, 2′-tetrahydropyranylor R¹⁰CO where R¹⁰ is as defined above

[0042] wherein when s is 0, R⁸ may also be O⁻ and R⁹ is ═CH₂ or ═C(H,C₁₋₆), ═C(H, aryl) or ═C(C₁₋₆)₂ and the nitrogen attached to the17-position is positively charged;

[0043] and pharmaceutically acceptable salts thereof.

[0044] According to another embodiment of the present invention is ahormonal or antihormonal steroid compound of structure II,

[0045] wherein

[0046] R¹ is (R² R³ N(O)_(r))—, where r is 0 or 1 and R² and R³ are eachindependently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, any of which may be optionally substituted; or

[0047] R¹ is

[0048] where q is 0 or 1, Y is —(CH₂)_(m)— where m is an integer of 0 to5, or Y is —(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p isan integer of 0 to 2, and Z is a heteroatom (optionally substituted) andwhere the CH₂ groups may be optionally substituted; or

[0049] R¹ is N-imidazolyl,- N-pyrrolyl-, halo-, HO—, CF₃SO₂O—, C₁₋₆alkyl O—, C₁₋₆ alkyl S—, C₁₋₆ alkyl S(O)—, C₁₋₆ alkyl S(O₂)—, C₁₋₆ alkylCO—, C₁₋₆ alkyl CH(OH)—, NC—, HCC—, C₆H₅CC—, 2′-furyl, 3′-furyl,2′-thiophenyl, 3′-thiophenyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl,2′-thiazolyl, 2′-N-methylimidazolyl, 5′-pyrimidinyl, C₆H₅—, H₂C═CH—,C₁₋₆ alkyl, or MeC(═CH₂)—;

[0050] R¹² is H or halo; or

[0051] R¹ and R¹² combine to form a ring

[0052] where W is CH₂, CH, NH, N, O, or S, and R⁴ is H or C₁₋₆ alkyl;

[0053] X is O or NOR⁵, where R⁵ is H or C₁₋₆ alkyl, C₃₋₈ cycloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₂ aryl, or heteroaryl, any of which maybe optionally substituted; or

[0054] X is (H, H), (H, OH), (H, OSi(C₁₋₆ alkyl)₃), or (H, OCOR⁵), whereR⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₂aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl, any of which may be optionallysubstituted;

[0055] X is

[0056] where Y is —(CH₂)_(m) where m is an integer of 0 to 3, or Y is—(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is an integerof 0 to 2 and Z is a heteroatom (optionally substituted) or Z is acarbon atom substituted with one or two C₁₋₆ alkyl groups;

[0057] R⁶ is H, C₁₋₆ alkyl or halogen;

[0058] s is 0 or 1;

[0059] R⁹ is H, C₁₋₆ alkyl C₂₋₆ alkenyl or C₂₋₆alkynyl, R¹⁰CO, OR¹¹, anyof which may be optionally substituted,

[0060] where R¹⁰ is H, C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,heteroaralkyl, heteroaralkenyl or heteroaralkynyl any of which may beoptionally substituted, and

[0061] where R¹¹ is H, C₁₋₆ alkyl, Si(C₁₋₆ alkyl)₃, 2′-tetrahydropyranylor R¹⁰CO where R¹⁰ is as defined above;

[0062] R¹³ and R¹⁴ are each independently H, C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl,C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl oraralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl orheteroaralkynyl, any of which may be optionally substituted; or R¹³ R¹⁴is O; and

[0063] R¹⁵ and R¹⁶ are each H or combine to form a group ═CH₂,optionally substituted,

[0064] and pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] A more complete appreciation of the invention and many of theattendant advantages thereof will be readily obtained as the same becomebetter understood by reference to the following detailed descriptionwhen considered in connection with the accompanying drawings, wherein:

[0066]FIG. 1 depicts a reaction scheme to prepare amine andhydroxylamine compounds according to the present invention;

[0067]FIG. 2 depicts a reaction scheme to prepare cyclic amine compoundsaccording to the present invention; and

[0068]FIG. 3 depicts a reaction scheme to prepare cyclic hydroxylaminecompounds according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] The above-identified compounds of formula I and II specificallyinclude compounds which are subsitituted on the A ring at the 3-positionwith two hydrogen atoms. These compounds are believed to undergooxidation in vivo to the corresponding carbonyl compound.

[0070] Within the scope of the present invention, the term heteroatommeans oxygen, nitrogen, sulfur, silicon or boron. Halogen meansfluorine, chlorine, bromine or iodine and halo means fluoro, chloro,bromo or iodo. Aralkyl, aralkenyl, or aralkynyl means a C₁-C₄ alkyl,C₂-C₄ alkenyl or C₂-C₄ alkynyl group bearing an aryl substituent. Loweralkyl means a C₁-C₆ alkyl group. Heteroaryl means a unit of 5 to 12non-hydrogen atoms consisting of one or more cyclic structures that maybe fused or linked together, which contain 1 to 5 heteroatoms and whichare generally accepted by those skilled in the art as having aromaticelectronic character.

[0071] Heteroaralkyl, heteroaralkenyl, or heteroaralkynyl means a C₁-C₄alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl group bearing a heteroarylsubstituent.

[0072] “Optionally substituted” means unsubstituted or substituted withone or more heteroatom(s) and/or halogens and/or alkyl groups of 1 to 4carbon atoms and/or alkenyl and/or alkynyl groups of 2 to 4 carbon atomsand/or cycloalkyl groups of 3 to 7 carbon atoms and/or aryl groups of 6to 12 carbon atoms and/or heteroaryl groups, and in which the alkyl,alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl group may be furthersubstituted with one or more heteroatoms and/or halogens. Substitutionmay occur directly on CH₂ groups of cyclic amine heterocycles. Wheretheir valency permits, heteroatoms may be substituted either within thecarbon chain or by attachment to it by single or double bonds. Forexample, —CH₂CH₂C(═O)H, —CH₂(C═O)CH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OH,CH₃CH₂CH₂O—, CH₂CH₂C(═O)NH₂, CH₃CH₂C(═O)NH—, —CH₂CH₂COOCH₃, CH₃CH₂COO—,and CF₃CC— all fall within this definition.

[0073] In all cases where valency and steric considerations permit,alkyl, alkenyl, alkynyl and cycloalkyl groups may contain additionaldouble or triple bonds and/or branched chains.

[0074] The group R⁶ at C₆ as it appears in structures I and II may be ineither the α or β position. In a preferred embodiment, the group R⁶ islocated in the α-position.

[0075] In another embodiment, the C₁₁β-aryl group may be replaced with apyridine group substituted with groups R¹ and R¹² as previouslydescribed.

[0076] In a preferred embodiment, the steroid having structure I issubstituted as follows: wherein

[0077] R¹-Ph is 4-aminophenyl, 4-(N-methylamino)phenyl,4-(N,N-dimethylamino)phenyl, 4-(N-piperidino)phenyl,4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl, 1-methylindol-5-yl or1-methyl-2,3-dihydroindol-5-yl or R¹-Ph is the N-oxide of4-(N,N-dimethyl)phenyl, 4-(N-piperidino)phenyl, 4-(N-pyrrolidino)phenyl,4-(N-morpholino)phenyl;

[0078] X is O, NOH, or NOCH₃;

[0079] R⁶ is H, CH₃, F or Cl;

[0080] R⁷ is H, methyl, ethynyl, 1-propynyl, 3-propynyl,3-hydroxypropyl, 3-hydroxy-1-propenyl (E- or Z-),3,3,3-trifluropropyn-1-yl, 3-hydroxypropyn-1-yl, (CH₂)₂COOCH₃,(CH₂)₂COOC₂H₅, (CH₂)₂COCH₃, CC—C₆H₅, CH₂C₆H₅, CN, or COOCH₃;

[0081] R⁸ is H, CH₃, or CH₂C₆H₅; and

[0082] R⁹ is H, OH, OCH₃, CHO, CH₃CO, C₆H₅CO or C₆H₅CH₂CO.

[0083] In a preferred embodiment, the compound of structure II issubstituted wherein,

[0084] R¹—Ph is 4-aminophenyl, 4-(N-methylamino)phenyl,4-(N,N-dimethylamino)phenyl, 4-(N-piperidino)phenyl,4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl, 1-methylindol-5-yl or1-methyl-2,3-dihydroindol-5-yl);

[0085] X is O, NOH, or NOCH₃;

[0086] R⁶is H, CH₃, F or Cl;

[0087] R⁹ is H, OH, CHO, CH₃CO, C₆H₅CO or C₆H₅CH₂CO;

[0088] R¹³ and R¹⁴ are O, (H, H), (H, CH₃) or (CH₃ CH₃); and

[0089] R¹⁵ and R¹⁶ (H, H) or combine to form (═CH₂).

[0090] In a preferred embodiment the spirocyclic amino group at C₁₇ ofthe compound of structure II is such that the amine nitrogen is situatedon the β-face of the compound, syn with the C₁₁ aryl group.

[0091] The compound of structure I, may also bear a nitrone functionalgroup, when s is 0, R⁸ is O⁻ and R⁹ is an alkene. In this case thenitrogen at the 17 position bears a positive charge.

[0092] Specific non-limiting examples include the compounds:11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxylamino)-17α-(1-propynyl)-estra-4,9-dien-3-one;11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxylamino)-17α-(1-propynyl)-estra-4,9-dien-3-one;11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estra-4,9-dien-3-one;11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estra-4,9-dien-3-one;17β-amino-11β-(4-(N,N-dimethylamino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one;17β-amino-11β-(4-(N-piperidino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one;17β-(N-acetamido)-11β-(4-(N,N-dimethylamino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one;17β-(N-acetamido)-11β-(4-(N-piperidino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one;11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(1-propynyl)estra-4,9-dien-3-one,and its N-oxide;17β-(N-formamido)-11β-(4-(N-piperidino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-oneand its N-oxide;11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxylamino)-17α-(3-hydroxypropyl)-estra-4,9-dien-3-one;11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxylamino)-17α-(3-hydroxypropyl)-estra-4,9-dien-3-one;11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one;11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one;17β-amino-11β-(4-(N,N-dimethylamino)phenyl)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one;17β-amino-17α-(3-hydroxypropyl)-11β-(4-(N-piperidino)phenyl)estra-4,9-dien-3-one;17β-(N-acetamido)-11β-(4-(N,N-dimethylamino)phenyl)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one;17β-(N-acetamido)-17α-(3-hydroxypropyl)-11β-(4-(N-piperidino)phenyl)estra-4,9-dien-3-one;11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one;17β-(N-formamido)-17α-(3-hydroxypropyl)-11β-(4-(N-piperidino)phenyl)estra-4,9-dien-3-one;11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(3-formyloxy-1-propyl)estra-4,9-dien-3-one;17β-(N-formamido)-17α-(3-formyloxy-1-propyl)-11β-(4-(N-piperidino)phenylestra-4,9-dien-3-one;11β-(4-(N,N-dimethylamino)phenyl)-1′-hydroxy-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N-piperidino)phenyl)-1′-hydroxy-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-N,N-dimethylamino)phenyl)-1′-hydroxy-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N-piperidino)phenyl)-1′-hydroxy-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N,N-dimethylamino)phenyl)-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N-piperidino)phenyl)-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N,N-dimethylamino)phenyl)-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N-piperidino)phenyl)-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N,N-dimethylamino)phenyl)-5′-oxo-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N-piperidino)phenyl)-5′-oxo-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one;11β-(4-(N,N-dimethylamino)phenyl)-1′-formyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-oneand11β-(4-(N-piperidino)phenyl)-1′-formyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one.

[0093] Those compounds of the present invention which bear an aminogroup may also comprise a salt formed with the amine. Suitablepharmaceutically acceptable salts are known to those of ordinary skillin the art and comprise carboxylates, sulfates, phosphates and halides.

[0094] The amino and hydroxylamino compounds of the present inventionmay be prepared from an intermediate hydroxy nitro compound of structure(III)

[0095] wherein

[0096] R¹ is (R² R³ N(O)_(r))—, where r is 0 or 1 and R² and R³ are eachindependently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, any of which may be optionally substituted; or

[0097] R¹ is

[0098] where q is 0 or 1, Y is —(CH₂)_(m)— where m is an integer of 0 to5, or Y is —(CH₂)_(m)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p isan integer of 0 to 2, and Z is a heteroatom (optionally substituted) andwhere any of the CH₂ groups may be optionally substituted; or

[0099] R¹ is N-imidazolyl-N-pyrrolyl-, H, halo-, HO—, CF₃SO₂O—, C₁₋₆alkyl-O—, C₁₋₆alkyl-S—, C₁₋₆ alkyl-S(O)—, C₁₋₆ alkyl-S(O₂)—, C₁₋₆alkyl-CO—, C₁₋₆ alkyl-CH(OH)—, NC—, HCC—, C₆H₅CC—, 2′-furyl, 3′-furyl,2′-thiophenyl, 3′-thiophenyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl,2′-thiazolyl, 2′-N-methylimidazolyl, 5′-pyrimidinyl, C₆H₅—, H₂C═CH—,C₁₋₆ alkyl, or MeC(═CH₂)—;

[0100] R¹² is H or halo; or

[0101] R¹ and R¹² combine to form a ring

[0102] where W is CH₂, CH, NH, N, O, or S, and R⁴ is H or C₁₋₆ alkyl;

[0103] where Y is —(CH₂)_(m)— where m is an integer of 0 to 3, or Y is—(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is an integerof 0 to 2 and Z is a heteroatom (optionally substituted) or Z is acarbon atom substituted with one or two C₁₋₆ alkyl groups;

[0104] R⁶ is H, C₁₋₆ alkyl or halogen;

[0105] R⁷ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl, any of which may be optionallysubstituted, CN, COOR¹⁰ or CONHR¹⁰, where R¹⁰ is H, C₁₋₈ alkyl, C₂₋₁₈alkenyl, C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl,aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl orheteroaralkynyl, any of which may be optionally substituted, byreduction of the nitro group, followed by hydrolysis of the ketal andelimination of the hydroxyl group. Such a method may be performed byconventional methods known to those of ordinary skill in the art. Forexample the nitro group may be reduced to an amine or hydroxylamine bytreatment with zinc and ammonium chloride. The product amine orhydroxylamine my be favored by adjustment of the ratio of zinc to nitrocompound, with lower molar ratios of zinc (2-18) favoring hyydroxylamineformation and higher ratios (20-80) favoring amine formation. Compoundsof structure III may be made by the method described in U.S. patentapplication entitled “17β-Nitro-11β-aryl Steroids and Their Derivativeshaving Agonist or Antagonist Hormonal Properties” by C. E. Cook, J. A.Kepler, R. S. Shetty, G. S Bartley and D. Lee, filed concurrently withthis application, (Attorney Docket No. 2025-0133-77), the relevantportions of which are hereby incorporated by reference.

[0106] Steroids having progestational, antiprogestational and/orantiglucocorticoid activity have use in the control of fertility inhumans and non-human mammals such as primates, domestic pets and farmanimals, and in the treatment of medical conditions in animals or humansin which these activities are beneficial. Thus they may be useful in thetreatment of conditions such as fibroids, Cushing's syndrome, glaucoma,endometriosis, cervical ripening prior to delivery, hormone replacementtherapy, premenstrual syndrome and cancer in addition to their use inthe control of fertility and reproduction.

[0107] The compounds of the present invention may be administered by avariety of methods. Thus, those products of the invention that areactive by the oral route may be administered in solutions, suspensions,emulsions, tablets, including sublingual and intrabuccal tablets, softgelatin capsules, including solutions used in soft gelatin capsules,aqueous or oil suspensions, emulsions, pills, lozenges, troches,tablets, syrups or elixirs and the like. Products of the inventionactive on parenteral administration may be administered by depotinjection, implants including Silastic™ and biodegradable implants,intramuscular and intravenous injections.

[0108] Compositions may be prepared according to any method known to theart for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents. Tablets containing the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor manufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate granulating anddisintegrating agents, such as maize starch, or alginic acid; bindingagents, such as starch, gelatin or acacia; and lubricating agents, suchas magnesium stearate, stearic acid or talc. Tablets may be uncoated ormay be coated by known techniques to delay disintegration and adsorptionin the gastrointestinal tract and thereby provide a sustained actionover a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

[0109] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, such as peanut oil, liquid paraffin or oliveoil.

[0110] Aqueous suspensions of the invention contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylethyl cellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Ophthalmic formulations, as is known inthe art, will be adjusted for osmotic pressure.

[0111] Oil suspensions may be formulated by suspending the activeingredient in a vegetable oil, such as arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. The oilsuspensions may contain a thickening agent, such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an antioxidant such as ascorbic acid.

[0112] Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water may beformulated from the active ingredients in admixture with a dispersing,suspending and/or wetting agent, and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose disclosed above. Additional excipients, for example sweetening,flavoring and coloring agents, may also be present.

[0113] The pharmaceutical composition of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, such as olive oil or arachis oil, a mineral oil, such as liquidparaffin, or a mixture of these. Suitable emulsifying agents includenaturally occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion may also contain sweetening and flavoring agents.

[0114] Syrups and elixirs may be formulated with sweetening agents, suchas glycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

[0115] The pharmaceutical compositions of the invention may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,such as a solution of 1,3-butanediol. Among the acceptable vehicles andsolvents that may be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils mayconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid may likewisebe used in the preparation of injectables. Sterilization may beperformed by conventional methods known to those of ordinary skill inthe art such as by aseptic filtration, irradiation or terminalsterilization (e.g. autoclaving).

[0116] Aqueous formulations (i.e oil-in-water emulsions, syrups, elixersand injectable preparations) may be formulated to achieve the pH ofoptimum stability. The determination of the optimum pH may be performedby conventional methods known to those of ordinary skill in the art.Suitable buffers may also be used to maintain the pH of the formulation.

[0117] The compounds of this invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenonirritating excipient which is solid at ordinary temperatures butliquid at the rectal temperatures and will therefore melt in the rectumto release the drug. Non-limiting examples of such materials are cocoabutter and polyethylene glycols.

[0118] They may also be administered by intranasal, intraocular,intravaginal, and intrarectal routes including suppositories,insufflation, powders and aerosol formulations.

[0119] Products of the invention which are preferably administered bythe topical route may be administered as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

[0120] Products having anti-glucocorticoid activity are of particularvalue in pathological conditions characterized by excess endogenousglucocorticoid such as Cushing's syndrome, hirsutism and in particularwhen associated with the adrenogenital syndrome, ocular conditionsassociated with glucocorticoid excess such as glaucoma, stress symptomsassociated with excess glucocorticoid secretion and the like.

[0121] Products having progestational activity are of particular valueas progestational agents, ovulation inhibitors, menses regulators,contraceptive agents, agents for synchronization of fertile periods incattle, endometriosis, and the like. When used for contraceptivepurposes, they may conveniently be admixed with estrogenic agents, suchas for example as ethynylestradiol or estradiol esters.

[0122] Products having anti-progestational activity are characterized byantagonizing the effects of progesterone. As such, they are of value incontrol of hormonal irregularities in the menstrual cycle and forsynchronization of fertile periods in cattle.

[0123] The compounds of the invention may be used for control offertility during the whole of the reproductive cycle. They are ofparticular value as postcoital contraceptives, for rendering the uterusinimical to implantation, and as “once a month” contraceptive agents.They may be used in conjunction with prostaglandins, oxytocics,estrogens and the like.

[0124] A further important utility for the products of the inventionlies in their ability to slow down growth of hormone-dependent cancers.Such cancers include kidney, breast, endometrial, ovarian cancers, andprostate cancer which are characterized by possessing progesteronereceptors and may be expected to respond to the products of thisinvention. Other utilities of anti-progestational agents includetreatment of fibrocystic disease of the breast. Certain cancers and inparticular melanomas may respond favorably to corticoid/anticorticoidtherapy.

[0125] The compounds according to the present invention may beadministered to any warm-blooded mammal such as humans, domestic pets,and farm animals. Domestic pets include dogs, cats, etc. Farm animalsinclude cows, horses, pigs, sheep, goats, etc.

[0126] The amount of active ingredient that may be combined with acarrier material to produce a single dosage form will vary dependingupon the disease treated, the mammalian species, and the particular modeof administration. A therapeutically effective amount may be determinedby routine experimentation and by analogy from the amounts used to treatthe same disease states with analogous steroid compounds. For example, aunit dose of the steroid may preferably contain between 0.1 milligramand 1 gram of the active ingredient. A more preferred unit dose isbetween 0.001 and 0.5 grams. For the specific treatment of endometriosisor fibroids an amount of 0.01 to 10 mg/kg of body weight, preferablyfrom 0.1 to 3 mg/kg may be administered. Similar dosages may be used forthe other therapeutic purposes of these compounds. Ordinarily thecompounds may be administered daily 1 to 4 times per day, preferably 1to 2 times per day, but for uses such as for example in hormonereplacement therapy, they may be administered in a cyclophasic regimen.In any case the frequency and timing of dosage will depend upon factorssuch as the half-life of the specific compound in the body, the dosageformulation and the route of administration. It will be understood,however, that the specific dose level for any particular patient willdepend on a variety of factors including the activity of the specificcompound employed; the age, body weight, general health, sex and diet ofthe individual being treated the time and route of administration; therate of excretion: other drugs which have previously been administered;and the severity of the particular disease undergoing therapy, as iswell understood by those of skill in the art.

[0127] Such compounds are useful in the treatment of endometriosis,uterine leiomyomas (fibroids) and certain cancers and tumors, in hormonereplacement therapy as well as in the control of various steps inreproduction and fertility, such as contraception. A more detaileddescription of the potential uses of such compounds is given inDonaldson, Molly S.; Dorflinger, L.; Brown, Sarah S.; Benet, Leslie Z.,Editors, Clinical Applications of Mifepristone (RU 486) and OtherAntiprogestins, Committee on Antiprogestins: Assessing the Science,Institute of Medicine, National Academy Press, 1993. They are alsouseful as intermediates for the synthesis of other steroids.

[0128] Having generally described this invention, a furtherunderstanding can be obtained by reference to certain general exampleswhich are provided herein for purposes of illustration only and are notintended to be limiting unless otherwise specified.

[0129] Synthetic Procedures

[0130] Compounds of this invention may be made according to proceduressuch as those outlined in FIGS. 1 to 3 beginning with11β-aryl-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17β-nitroestr-9-enes(e.g., compound A-1 of FIG. 1 or analogous compounds) or with3′,4′-dihydro-11β-aryl-3,3-[1,2-ethanediylbis(oxy)]-1′-oxo-spiro[estr-9-en-17β,2′(2′H)-pyrrole]-5α-ols(e.g., compound C-1 of FIG. 3 or analogous compounds). Compounds of thetype A-1 or C-1 may be prepared according to the procedures given inU.S. patent application entitled “17β-Nitro-11β-aryl Steroids and TheirDerivatives having Agonist or Antagonist Hormonal Properties” by C. E.Cook, J. A. Kepler, R. S. Shetty, G. S Bartley and D. Lee, filedconcurrently with this application, (Attorney Docket No. 2025-0133-77).

[0131] Thus for example, treatment of A-1 with excess zinc dust(preferably around 9 atom-equivalents) and ammonium chloride inethanol/water solution at around room temperature leads in good yield tothe 17β-N-hydroxylamino compound A-2, which upon treatment with aqueousacid (preferably trifluoroacetic acid in water and CH₂Cl₂) undergoesketal hydrolysis and dehydration to the 4,9-dien-3-one A-3. If theintermediate hydroxylamine A-2 is treated with formalin and NaBH₃CN, thenitrogen is methylated to form intermediate 17β-N-methyl-N-hydroxycompound A-5, which can be hydrolyzed and dehydrated in the same manneras A-2 to yield the dienone A-7.

[0132] If compound A-1 is treated with excess zinc dust (preferablyaround 60 atom-equivalents) and ammonium chloride inethanol/water/tetrahydrofuran (THF) solution at elevated temperatures(preferably around 70° C.), reduction of the nitro group leads to the17β-amines A-4. These compounds could be hydrolyzed and dehydrated asdescribed above to yield the dienones A-6. The amino group of A-6 may befirther derivatized, for example by conversion to amides by methods wellknown to those skilled in the art. For example treatment of A-6 withformic acid and N,N-dicyclohexylcarbodiimide (DCC) leads to theformamido compounds, whereas treatment with acetic anhydride in pyridineresults in the formation of acetamido compounds.

[0133] If R⁷ of compound A-1 terminates in a carboxyl or carboxyl esterfunction and the chain length permits, then reduction of the nitro groupcan lead to cyclization to the amide. Thus if R⁷ is CH₂CH₂COOEt(compound B-1) and excess zinc is used for the reduction at elevatedtemperature, the cyclic amide B-2 is formed. Acid hydrolysis anddehydration then leads to dienone B-3. If R⁷ of compound A-1 contains acarbonyl group (ketone or aldehyde) at an appropriate position in thechain, then reduction under milder conditions leads to the spironitronessuch as compound C-1, the preparation of which is described in U.S.patent application entitled “17β-Nitro-11β-aryl Steroids and TheirDerivatives having Agonist or Antagonist Hormonal Properties” by C. E.Cook, J. A. Kepler, R. S. Shetty, G.S Bartley and D. Lee, filedconcurrently with this application, (Attorney Docket No. 2025-0133-77).Reduction of the nitrone with, for example, sodium borohydride resultsin the N-hydroxyspiropyrrolidines C-2, which may also be hydrolyzed anddehydrated to the dienones as described above.

[0134] Compounds such as B-2 and C-2 are versatile intermediates, whichcan be converted to a variety of novel compounds by methods known tothose skilled in the art, including N- or O-alkylation and/or reductionby hydride reagents to yield for example, cyclic amines, which can befurther modified, e.g., by N-alkylation or N-acylation. Thus can beobtained various spiropyrrolidines analogs of B-2, B-3, C-2 and C-3.

[0135] Having generally described this invention, a furtherunderstanding can be obtained by reference to certain specific exampleswhich are provided herein for purposes of illustration only and are notintended to be limiting unless otherwise specified.

[0136] General Procedures. Unless otherwise stated, reagent-gradechemicals were obtained from commercial sources and were used withoutfurther purification. Ether and tetrahydrofuran (THF) were freshlydistilled from sodium benzophenone ketyl pair under nitrogen. Allmoisture- and air-sensitive reactions and reagent transfers were carriedout under dry nitrogen or argon. Thin layer chromatography (TLC) wasperformed on EM Science precoated silica gel 60 F-254 plates. Compoundswere normally visualized by UV light (254 nm) or p-anisaldehyde spray.Preparative column chromatography employed EM Science silica gel, 60 Å(230-400 mesh). Solutions were concentrated by use of a rotaryevaporator under water aspirator pressure at ambient temperature.Melting points were taken on a Mel-Temp II and are uncorrected. Unlessotherwise noted, ¹H NMR spectra were obtained at 250 MHz on a Bruker AC250 spectrometer in CDCl₃ as solvent with tetramethylsilane (TMS) asinternal standard. Chemical shifts are reported in units of ppmdownfield from TMS. Mass spectra were normally obtained by electronimpact at 70 eV on a Hewlett Packard 5989A instrument. Elementalanalyses were performed by Atlantic Microlab Inc., Atlanta, Ga.

EXAMPLE 1 Synthesis of 11β-[4-(N,N-Dimethylamino)phenyl]-17β-(N-hydroxylamino)-17α-(1-propynyl)estra-4,9-dien-3-one [A-3 (R¹=4-Me₂N—, R⁷═CH₃CC—,R⁶═R¹²═H)]

[0137]11β-[4-(N,N-Dimethylamino)phenyl]-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17β-(N-hydroxylamino)-17α-(1-propynyl)estr-9-ene[A-2 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]. To a homogeneous solution of6.34 g (12.2 mmol) of nitropropyne A-1 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)and 1.37 g (25.6 mmol) of NH₄Cl in 160 mL of THF, 80 mL of EtOH, and 80mL of water at room temperature was added 7.17 g (110 mmol) of zinc dust(−325 mesh). After stirring for 1.5 h, the mixture was filtered througha pad of Celite with the aid of EtOAc. The filtrate was washed threetimes with brine, dried over Na₂SO₄, filtered, and the solvent wasremoved under reduced pressure to afford a white amorphous solid (6.42g). Chromatography on silica gel (70% EtOAc in hexanes) affordedhydroxylamine A-2 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H) (3.60 g, 60% yield).¹H NMR (250 MHz, CDCl₃) δ7.05 (2H, d, J=8.6 Hz), 6.64 (2H, d, J=8.8 Hz),5.02 (1H, br s), 4.43 (1H, s), 4.21 (1H, d, J=6.2 Hz), 4.02-3.92 (4H,m), 2.90 (6H, s), 1.91 (1H, s), 0.48 (3H, s).

[0138]11β-[4-(N,N-Dimethylamino)phenyl]-17β-(N-hydroxylamino)-17α-(1-propynyl)estra-4,9-dien-3-one[A-3 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]. A mixture of 3.60 g (7.11 mmol)of hydroxyketal A-2 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H) in 316 mL ofCH₂Cl₂ and 6.3 mL of water was stirred vigorously while cooling in anice-water bath for 1.5 h. To the rapidly stirred dispersion was addeddropwise 8.80 mL (114 mmol) of trifluoroacetic acid. After stirringvigorously for 3 h, excess saturated aqueous NaHCO₃ solution was addedslowly and the mixture was allowed to stir at room temperature for 20min. The aqueous layer was separated and extracted three times withEtOAc. The combined organic solutions were washed twice with brine,dried over Na₂SO₄, filtered, and the solvent was removed under reducedpressure to give a yellow solid (3.11 g). The material waschromatographed on silica gel (70% EtOAc in hexanes). Combination of theresulting fractions of >97% purity (as determined by HPLC analysis)afforded hydroxylamine dienone A-3 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)(2.37 g, 75% yield) [mp 100-117° C. (amorphous)]. The sample could bedried in vacuo at 92° C. for 14 h to provide solvent-free product withno loss of purity. ¹H NMR (250 MHz, CDCl₃) δ7.01 (2H, d, J=8.5 Hz), 6.65(2H, d, J=8.9 Hz), 5.75 (1H, s), 5.16 (1H, br s), 4.65 (1H, s), 4.31(1H, br s), 2.91 (6H, s), 1.94 (3H, s), 0.55 (3H, s). Anal. Calcd. forC₂₉H₃₆N₂O₂.0.5 H₂O: C, 76.79; H, 8.22; N, 6.18. Found: C, 76.82; H,8.29; N, 6.12. MS m/z (rel inten) 444 (M⁺, 12), 428 (12), 411 (23), 134(51), 121 (100).

EXAMPLE 2 Synthesis of11β-[4-(N,N-Dimethylamino)phenyl]-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estra-4,9-dien-3-one[A-7 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]

[0139]11β-[4-(N,N-Dimethylamino)phenyl]-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estr-9-ene[A-5 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]. To a solution of 232 mg (0.458mmol) of hydroxylamine A-2 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H) in 4.6 mLof CH₃CN at room temperature was added 0.19 mL (2.3 mmol) of formalin,then 49 mg (0.733 mmol) of NaBH₃CN. After 45 min, the whiteprecipitate-containing basic reaction mixture [pH 8-9 (as determined bypre-H₂O-wetted pH paper)] was brought to pH 7 by the addition of threesmall portions (ca. 1 drop total) of glacial acetic acid, thus causinghomogeneity. After 1.5 h, the solution was measured to be pH 8, thenanother small amount (ca. 0.25 drop) of glacial acetic acid was added,then 40 min later, saturated aqueous NaHCO₃ and EtOAc were added. Theaqueous layer was separated and extracted three times with EtOAc. Thecombined organic solutions were washed twice with brine, dried overNa₂SO₄, filtered, and the solvent was removed under reduced pressure.The resulting white foam was purified by chromatography on silica gel(60% EtOAc in hexanes) to afford N-methylhydroxylamine A-5 (R¹=4-Me₂N—,R⁷═CH₃CC—, R⁶═R¹²═H) (74 mg, 31% yield). ¹H NMR (250 MHz, CDCl₃) δ7.04(2H, d, J=8.7 Hz), 6.63 (2H, d, J=8.7 Hz), 4.42 (1H, s), 4.16 (1H, brs), 4.02-3.92 (4H, m), 2.89 (6H, s), 2.54 (3H, s), 1.96 (3H, s), 0.51(3H, s).

[0140]11β-[4-(N,N-Dimethylamino)phenyl]-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estra-4,9-dien-3-one[A-7 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]. To a vigorously stirred mixtureof 122 mg (234 mmol) of N-methylhydroxylamine ketal A-5 (R¹=4-Me₂N—,R⁷═CH₃CC—, R⁶═R¹²═H) in 10.2 mL of CH₂Cl₂ and 0.5 mL of CDCl₃ and 0.21mL of water at 0° C. was added dropwise 0.29 mL (3.76 mmol) oftrifluoroacetic acid. After stirring vigorously for 5.5 h at 0° C.,saturated aqueous NaHCO₃ was added and the mixture was stirred for 30min, then diluted with EtOAc. The aqueous layer was separated andextracted three times with EtOAc. The combined organic solutions werewashed twice with brine, dried over Na₂SO₄, filtered, and the solventwas removed under reduced pressure, giving a yellow foam (118 mg). Theproduct was purified by flash chromatography on silica gel (80% EtOAc inhexanes), then by flash chromatography on silica gel (1.1:30:68.9,MeOH-THF-hexanes), then by medium pressure chromatography on silica gel(hexanes, then 30% THF in hexanes), and then by reverse-phasepreparative HPLC (20% H₂O in MeOH) to afford methylhydroxylamine dienoneA-7 (R¹=4-Me₂N—, R¹═CH₃CC—, R⁶═R¹²═H) (29.0 mg, 27% yield) in >97%purity, as determined by HPLC analysis. ¹H NMR (250 MHz, CDCl₃) δ7.00(2H, d, J=8.5 Hz), 6.65 (2H, d, J=8.8 Hz), 5.75 (1H, s), 4.28 (1H, d,J=6.4 Hz), 2.91 (6H, s), 2.57 (3H, s), 1.98 (3H, s), 0.58 (3H, s). Anal.Calcd. for C₃₀H₃₈N₂O₂.0.75 H₂O: C, 76.32; H, 8.43; N, 5.93. Found: C,76.62; H, 8.17; N, 5.87. MS m/z (rel inten) 458 (M⁺, 13), 441 (32), 411(21), 320 (24), 278 (23), 225 (23), 121 (100).

EXAMPLE 3 Synthesis of17β-Amino-11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propynyl)estra-4,9-dien-3-one[A-6 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]

[0141]17β-Amino-11β-[4-(N,N-dimethylamino)phenyl]-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17α-(1-propynyl)estr-9-ene[A-4 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]. To a homogeneous solution of5.00 g (9.60 mmol) of nitropropyne A-1 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)and 10.3 g (192 mmol) of NH₄Cl in 100 mL of THF, 50 mL of EtOH, and 50mL of water at 70° C. was added 37.7 g (576 mmol) of zinc dust (−325mesh). After stirring efficiently for 7.5 h, the mixture was allowed tocool to room temperature and was suction filtered through a pad ofCelite with the aid of EtOAc. The filtrate was washed three times withbrine, dried over Na₂SO₄, filtered, and the solvent was removed underreduced pressure to give a yellow foam (4.95 g). Chromatography onsilica gel (20% MeOH in EtOAc) provided aminopropyne A-4 (R¹=4-Me₂N—,R⁷═CH₃CC—, R⁶═R¹²═H) (3.48 g, 74% yield). ¹H NMR (250 MHz, CDCl₃) δ7.06(2H, d, J=8.5 Hz), 6.64 (2H, d, J=8.8 Hz), 4.42 (1H, br s), 4.25 (1H, d,J=6.9 Hz), 4.03-3.90 (4H, m), 2.91 (6H, s), 1.84 (3H, s), 0.40 (3H, s).

[0142]17β-Amino-11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propynyl)estra-4,9-dien-3-one[A-6 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H)]. A mixture of 265 mg (0.540mmol) of aminopropyne ketal A-4 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H) in 24mL of CH₂Cl₂ and 0.48 mL of water was stirred vigorously in an ice-waterbath for 1.5 h. To the rapidly stirred dispersion was added dropwise0.67 mL (8.69 mmol) of trifluoroacetic acid. After stirring vigorouslyfor 4.5 h, excess saturated aqueous NaHCO₃ solution was added slowly,then the mixture was stirred for 30 min at room temperature. The aqueouslayer was separated and extracted three times with brine, dried overNa₂SO₄, filtered, and the solvent was removed under reduced pressure togive a yellow oil (258 mg). The material prepared in this fashion washighly pure by ¹H NMR analysis, and in analogous experiments could beused in subsequent transformations without further purification. Asample of >97% purity (as determined by HPLC analysis) was prepared bychromatography on silica gel (12% MeOH in EtOAc), then by chromatographyon silica gel (10% MeOH in EtOAc), then by chromatography onEt₃N-deactivated silica gel (50% EtOAc in hexanes), and thenchromatographed by reverse-phase preparative HPLC [30% H₂O in MeOHcontaining Et₃N (50 mM)] to afford dienone A-6 (R¹=4-Me₂N—, R⁷═CH₃CC—,R⁶═R¹²═H) (44.6 mg, 19% yield). ¹H NMR (250 MHz, CDCl₃) δ7.03 (2H, d,J=8.7 Hz), 6.66 (2H, d, J=8.9 Hz), 5.76 (1H, s), 4.36 (1H, d, J=7.3 Hz),2.92 (6H, s), 1.84 (3H, s), 0.48 (1H, s). Anal. Calcd. for C₂₉H₃₆N₂O: C,81.27; H, 8.47; N, 6.54. Found: C, 81.21; H, 8.50; N, 6.49. MS m/z (relinten) 428 (M⁺, 61), 411 (97), 278 (33), 134 (100).

EXAMPLE 4 Synthesis of17β-(N-Acetamido)-11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propynyl)estra-4,9-dien-3-one[A-8 (R¹=4-Me₂N—, R⁷═CH₃CC—, R¹⁰═CH₃, R⁶═R¹²═H)]

[0143] To a solution of 72 mg (0.168 mmol) of aminodienone A-6(R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H) in 1.6 mL of pyridine at 0° C. wasadded 18.0 mL (185 mmol) of Ac₂O. After 2.5 h, one drop of Ac₂O wasadded, and after 30 min, the solution was partially concentrated under aslow stream of nitrogen. The resulting yellow-brown oil was combinedwith 19 mg of previously obtained product, then chromatographed onsilica gel (90% EtOAc in hexanes) to give dienone acetamide A-8(R¹=4-Me₂N—, R⁷═CH₃CC—, R¹⁰═CH₃, R⁶═R¹²═H) (64.8 mg) as a solid. Threesubsequent reverse-phase MPLC purifications (80:20, MeOH—H₂O, 75:25,MeOH—H₂O, and 77.5:22.5, MeOH—H₂O) afforded dienone A-8 (R¹═4-Me₂N—,R¹⁰═CH₃, R⁷═CH₃CC—, R⁶═R¹²═H) (37.7 mg, 38% yield [adjusted]) in >97%purity as determined by HPLC analysis. ¹H NMR (250 MHz, CDCl₃) δ7.03(2H, d, J=8.6 Hz), 6.70 (2H, d, J=8.8 Hz), 5.67 (1H, s), 5.55 (1H, brs), 4.36 (1H, d, J=6.2 Hz), 2.92 (6H, s), 1.93 (3H, s), 1.87 (3H, s),0.49 (3H, s). Anal. Calcd. for C₃₁H₃₈N₂O₂.0.5 H₂O: C, 77.63; H, 8.20; N,5.84. Found: C, 77.30; H, 8.20; N, 5.77. MS m/z (rel inten) 470 (M⁺,100), 411 (9), 280 (44), 121 (41).

EXAMPLE 511β-[4-(N,N-Dimethylamino)phenyl]-17β-(N-formamido)-17α-(1-propynyl)estra-4,9-dien-3-one[A-8 (R¹=4-Me₂N—, R⁷═CH₃CC—, R¹⁰═R⁶═R¹²═H)]

[0144] To a solution of 2.11 g (10.2 mmol) of dicyclohexylcarbodiimidein 11 mL of CHCl₃ at room temperature was added 20.4 mL (20.4 mmol) of1.00 M formic acid in CHCl₃, causing a white precipitate. After 45 min,the mixture was added to a solution of 2.19 g (5.11 mmol) ofaminopropyne A-6 (R¹=4-Me₂N—, R⁷═CH₃CC—, R⁶═R¹²═H) and 2.47 mL (30.7mmol) of pyridine in 22 mL of CHCl₃. After 20 min, 66 mL of ether wasadded and the resulting mixture was filtered through a pad of Celite,rinsing six times with 10 mL of ether. The filtrate was concentratedunder reduced pressure, then diluted with 22 mL of EtOAc and stirred for10 min. The resulting mixture was filtered through a pad of Celite,rinsing eight times with 3 mL of EtOAc. The filtrate was concentratedunder reduced pressure. The residue was iteratively diluted three timeswith 11 mL of toluene and concentrated under reduced pressure by rotaryevaporation. After further solvent removal in vacuo, the light greenresidue was free of pyridine by ¹H NMR analysis and was chromatographedon silica gel (75% EtOAc in hexanes) to afford formamide A-8(R¹=4-Me₂N—, R⁷═CH₃CC—, R¹⁰═R⁶═R¹²═H) (1.56 g, 67% yield) [mp 128-142°C. (amorphous)]. The product was determined to be >97% pure by HPLCanalysis, and could be heated in vacuo at 90° C. for 16 h to providesolvent-free product, with conservation of >97% purity by HPLC analysis.This compound existed as a mixture of equilibrating forms (observable by¹H NMR). ¹H NMR (250 MHz, CDCl₃, integration adjusted for ratio of majorand minor forms) δ8.52 (1H, d, J=11.7 Hz), 6.98 (2H, d, J=8.6 Hz), 6.64(2H, d, J=8.8 Hz), 6.21 (1H, d, J=11.8 Hz), 5.77 (1H, s), 4.37 (1H, d,J=6.7 Hz), 2.91 (6H, s), 1.90 (3H, s), 0.47 (3H, s); minor form: 8.08(1H, s), 7.04 (shoulder), 5.68 (1H, s), 1.88 (3H, s), 0.50 (shoulder).Anal. Calcd. for C₃₀H₃₆N₂O₂.1.25 H₂O: C, 75.20; H, 8.10; N, 5.85. Found:C, 75.17; H, 7.56; N, 5.80. MS m/z (rel inten) 456 (M⁺, 94), 280 (44),134 (51), 121 (100).

EXAMPLE 6 Synthesis of17β-Amino-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)phenyl]estra-4,9-diene-3-one [A-6 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH,R⁶═R¹²═H)]

[0145] 3,3-[1,2-Ethanediylbis(oxy)]-5α,10α-oxidoestr-9(11)-en-17-one. Toa solution of 32.0 g (102 mmol) of3,3-[1,2-ethanediylbis(oxy)]estra-5(10),9(11)-dien-17-one in 192 mL ofCH₂Cl₂ at 0° C. was added 7.04 mL (50.9 mmol) of hexafluoroacetonetrihydrate (Lancaster Synthesis, Inc.) followed by 2.46 g (17.3 mmol) ofNa₂HPO₄, and then 8.64 mL (153 mmol) of 50% H₂O₂ was added dropwise tothe efficiently stirred mixture (overhead mechanical stirring).Efficient stirring was continued for 18 h, during which time thetemperature was allowed to gradually rise to room temperature, then 192mL of saturated aqueous Na₂S₂O₃ was added. After stirring for 20 min,the mixture was combined with another (32.0 g) batch which had beenprepared identically up to this point in parallel. The aqueous layer(bottom) was separated and extracted three times with 80 mL of EtOAc.The combined organic solutions were diluted with 240 mL of EtOAc andwashed twice with 80 mL of saturated aqueous NaHCO₃ solution, twice with80 mL of brine, dried over MgSO₄, filtered, and the solvent was removedunder reduced pressure. The yellow solid (76.1 g) was triturated with320 mL of diethyl ether with magnetic stirring for 12 h in a closedflask. The resulting white slurry was combined with three other batches(3×32.0 g) which had been prepared identically (and proportionally) tothis point, in parallel, then suction filtered through a coarse-porositysintered glass funnel, rinsing three times with 40 mL of diethyl ether,then allowed to suck dry for 1.5 h. The resulting white filter cake wasgently scraped into a fine white powder and dried in vacuo to afford thedesired epoxide of high purity (89.5 g, 53% yield). ¹H NMR (250 MHz,CDCl₃) δ6.06 (1H, br s), 3.98-3.88 (4H, m), 2.52-2.44 (2H, m), 1.32-1.12(1H, m), 0.88 (3H, s).

[0146] 1-(4-Bromophenyl)piperidine. To a solution of 320 g (1.86 mmol,1.00 eq) of 4-bromoaniline in 1.20 L of toluene at room temperature in a5 L round bottomed flask equipped with an overhead mechanical stirrerwas added 648 mL (3.72 mmol, 2.00 eq) of diisopropylethylamine then 253mL (1.86 mmol, 1.00 eq) of 1,5-dibromopentane followed by rinsing with200 mL of toluene. With a heating mantle, the efficiently stirredsolution was heated to 100° C. to 115° C., as determined by athermometer immersed in the reaction solution. After 10 h, highconversion to desired product was observed by TLC analysis. Theresulting voluminous precipitate-containing brown mixture was allowed tocool to room temperature. The mixture was crushed with a spatula into atransferable slurry with the aid of 390 mL of toluene. Thediisopropylethylamine hydrochloride solids were removed by suctionfiltration through a coarse porosity fritted funnel followed by rinsingthe solids with toluene (3×320 mL). (Further toluene rinses of theresulting brown solids yielded only an insignificant amount ofmaterial.) Rotary evaporation under reduced pressure of the brownfiltrate followed by further solvent removal in vacuo for 12 h at roomtemperature afforded a soft brown solid (398 g, 89% crude yield) whichwas crushed into small pieces. 20.0 g of this crude material was removedfor experimental optimization, resulting in the following purificationprotocol.

[0147] To the remainder of the crude product (378 g) was added, in five300 mL portions, 1.50 L of diethyl ether with efficient magneticstirring. After 30 min. at room temperature, stirring was discontinuedand the stir bar was removed. A dark insoluble fine solid was allowed tosettle, and the brown solution was carefully decanted, rinsing the brownsolids with diethyl ether (3×100 mL). To the combined brown etherealsolutions at room temperature was added 38.5 mL (406 mmol) of aceticanhydride. After stirring for 3 h at room temperature, 300 mL of aqueous10% hydrochloric acid (i.e. 3.7% HCl_((aq))) was added at roomtemperature and the mixture was efficiently stirred for 5 min, duringwhich time a small amount of a yellow precipitate formed. The etherlayer was separated and extracted with aqueous 10% hydrochloric acid(5×300 mL). The combined acidic aqueous solutions were decanted toremove a small amount of a yellow solid and then back-extracted oncewith 150 mL of diethyl ether. The aqueous solution was basified to pH 10with efficient stirring at room temperature by the slow addition of 235mL of concentrated ammonium hydroxide over 20 min. To the resultingyellow/white precipitate-containing mixture was added 600 mL of diethylether with rapid stirring, thus completely dissolving the solids afterca. 10 min. The aqueous layer was separated and extracted with diethylether (2×150 mL). The combined ethereal solutions were washed with brine(2×150 mL), dried over Na₂SO₄, filtered, and the solvent was removed byrotary evaporation under reduced pressure. Further solvent removal invacuo for 12 h afforded the highly pure product as an off-white solid[338 g, 80% yield (adjusted for the 20.0 g removal)]. ¹H NMR (250 MHz,CDCl₃) δ7.29 (2H, d, J=9.1 Hz), 6.76 (2H, d, J=9.1 Hz), 3.11-3.07 (4H,m), 1.73-1.66 (4H, m), 1.59-1.51 (2H, m).

[0148]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-11β-[4-(N-piperidino)phenyl]estr-9-en-17-one.A 3 L round-bottomed flask equipped with an overhead mechanical stirrerand charged with 9.67 g (398 mmol) of magnesium turnings was flame-driedunder a stream of dry nitrogen. After cooling to room temperature, 333mL of THF was added followed by a few crystals of iodine, thus impartinga light brown coloration. To the efficiently stirred mixture was added40 mL of a solution of 91.9 g (383 mmol) of 1-(4-bromophenyl)piperidinein 333 mL of THF. After heating the mixture to reflux for ca. 5 min, theiodine color quickly faded to colorless, at which time the mixture wasallowed to cool nearly to room temperature. The remainder of the bromidesolution was added dropwise over a period of 1.5 h. The mixture was thencooled in an ice-water bath for 1.8 h, then 15.1 g (153 mmol) of finelypowdered CuCl was added in one portion. After the mixture was stirredefficiently for 60 sec, a solution of 50.6 g (153 mmol) of3,3-[1,2-ethanediylbis(oxy)]-5α,10α-oxidoestr-9(11)-en-17-one in 380 mLof THF was added (poured in) over 30 sec, causing the formation of avoluminous light yellow precipitate. After 10 min, 250 mL of saturatedaqueous NH₄Cl solution was slowly added, followed by 630 mL of EtOAc.After stirring for 30 min, the mixture was diluted and stirred with 300mL of water. The aqueous layer was separated and extracted three timeswith 250 mL of EtOAc. The combined organic solutions were washed threetimes with 250 mL of brine, dried over MgSO₄, filtered, and the solventwas removed under reduced pressure. The resulting material (116 g) wascombined with an analogously prepared batch of crude product (11.3 g) in55 mL of CH₂Cl₂, then chromatogtaphed on silica gel (elution ofpiperidinophenyl reagent by-product with CH₂Cl₂, then elution of productwith 60% EtOAc in hexanes) to afford the desired product, in which somefractions contained a minor amount of a bis-adduct in which Grignardreagent had undergone addition to the 17-carbonyl group. Thus, anotherchromatography of the concentrated contaminated fractions on silica gel(60% EtOAc in hexanes) with combination of the resulting pure fractionswith the pure fractions from the first chromatographic separationafforded contaminant-free product (65.2 g, 79% adjusted yield). ¹H NMR(250 MHz, CDCl₃) δ7.07 (2H, d, J=8.6 Hz), 6.83 (2H, d, J=8.7 Hz), 4.53(1H, s), 4.30 (1H, d, J=6.8 Hz), 4.02-3.92 (4H, m), 3.13-3.08 (4H, m),0.50 (3H, s).

[0149]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-11β-[4-(N-piperidino)phenyl]estr-9-en-17-oxime.To a solution of 65.1 g (132 mmol) of3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-11β-[4-(N-piperidino)phenyl]estr-9-en-17-onein 450 mL of anhydrous pyridine at room temperature under nitrogen wasadded 15.2 g (218 mmol) of hydroxylamine hydrochloride. After stirringfor 19.5 h, 1.50 L of water and 475 mL of EtOAc were added. Afterstirring for 10 min, the aqueous layer was separated and extracted threetimes with 275 mL of EtOAc. The combined organic solutions were washedtwice with 275 mL of brine, dried over Na₂SO₄, filtered, and the solventwas removed under reduced pressure. The resulting foam was iterativelyrotary evaporated under reduced pressure three times with 275 mL oftoluene at 40° C., during which time 4.93 g of analogously preparedmaterial was combined. Further solvent was removed in vacuo, thusaffording the desired oxime as a yellow foam (81.7 g) free of pyridineby ¹H NMR analysis. The material was carried on without furtherpurification. ¹H NMR (250 MHz, CDCl₃) δ8.37 (1H, br s), 7.08 (2H, d,J=9.0 Hz), 6.81 (2H, d, J=8.6 Hz), 4.37 (1H, s), 4.22 (1H, d, J=6.6 Hz),4.08-3.89 (4H, m), 3.12-3.08 (4H, m), 0.54 (3H, s).

[0150]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-11β-[4-(N-piperidino-N-oxide)phenyl]estr-9-en-17-oxime.To a solution of 81.7 g (148 mmol assumed) of 3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-11β-[4-(N-piperidino)phenyl]estr-9-en-17-oxime in 290mL of CH₂Cl₂ at 0° C. was added 10.3 mL (73.7 mmol) of hexafluoroacetonetrihydrate. With vigorous stirring, 17.8 mL (310 mmol) of 50% H₂O₂ wasadded dropwise. The mixture was stirred vigorously for 14.5 h, duringwhich time the mixture had gradually warmed to room temperature. Water(414 mL) and EtOAc (1.65 L) were added, and the resulting mixture wasstirred well for 20 min. The organic layer was separated and extractedfive times with 125 mL of water. The combined aqueous solutions werecarried on to the next step without further manipulation. A smallaliquot could be concentrated in vacuo for characterization: ¹H NMR (250MHz, CDCl₃) δ10.7 (1H, br s), 7.96 (2H, d, J=8.6 Hz), 7.36 (2H, d, J=8.6Hz), 4.39-4.32 (1H, m), 4.05-3.97 (4H, m), 3.68-3.56 (2H, m), 3.44-3.39(2H, m), 0.49 (3H, s).

[0151]17-Bromo-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17-nitro-11β-[4-(N-piperidino)-phenyl]estr-9-ene[A-1 (R¹=4-(N-piperidino)-, R⁷═Br, R⁶═R¹²═H)]. To a solution of 65.9 g(369 mmol) of N-bromosuccinimide (NBS) in 375 mL of 1,4-dioxane at roomtemperature was added a solution of 37.0 g (369 mmol) of KHCO₃ in 375 mLof water. After 5 min, the above aqueous solution of3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-11β-[4-(N-piperidino-N-oxide)phenyl]estr-9-en-17-oximeat room temperature was diluted with 720 mL of 1,4-dioxane, then slowlyadded to the NBS-KHCO₃ solution at such a rate so as to avoid excessivegas evolution and foaming. After stirring the solution at roomtemperature for 16 h, 262 g (944 mmol) of FeSO₄.7H₂O was added, causinga voluminous brown precipitate, then 375 mL of EtOAc and 650 mL of waterwere added. After stirring efficiently for 30 min, the aqueous layer wasseparated and extracted four times with 300 mL of EtOAc. The combinedorganic solutions were washed twice with 300 mL of brine, dried overNa₂SO₄, filtered, and the solvent was removed under reduced pressure toafford A-1 (R¹=4-(N-piperidino)-, R⁷═Br, R⁶═R¹²═H) as a brown foam (69.3g), which was used directly in the next step without purification. ¹HNMR (250 MHz, CDCl₃) δ7.07 (2H, d, J=7.5 Hz), 6.87 (2H, m), 4.42 (1H,s), 4.32 (1H, d, J=6.0 Hz), 4.03-3.93 (4H, m), 3.43-3.28 (1H, m), 3.12(4H, br s), 0.48 (3H, s).

[0152]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-17β-nitro-11β-[4-(N-piperidino)phenyl]estr-9-ene[A-1 (R¹=4-(N-piperidino)-, R⁶═R¹═R¹²═H)]. To a well-stirred solution of69.3 g of the above crude bromide [A-1 (R¹=4-(N-piperidino)-, R⁷═Br,R⁶═R¹²═H)] in 1.17 L of THF and 230 mL of water at room temperature wasadded 14.4 g (380 mmol) of NaBH₄ in small portions over a period of 1 h.After an additional 1 h, a solution of of 84.3 g (1.21 mol) ofhydroxylamine hydrochloride in 585 mL of water was carefully added.After 15 min, the aqueous layer was separated and extracted three timeswith 116 mL of EtOAc. The combined organic solutions were washed threetimes with 116 mL of brine, dried over Na₂SO₄, filtered, and the solventwas removed under reduced pressure to afford a yellow foam (56.2 g). Thematerial was taken up in a minimal amount of CH₂Cl₂ and chromatographedon silica gel (55% EtOAc in hexanes) to afford nitro intermediate A-1(R¹=4-(N-piperidino)-, R⁶═R¹═R¹²═H) (33.3 g, 45% yield for 5 steps) as ayellow solid. ¹H NMR (250 MHz, CDCl₃) δ7.04 (2H, d, J=8.6 Hz), 6.81 (2H,d, J=8.8 Hz), 4.38 (1H, s), 4.33 (1H, t, J=11 Hz), 4.23 (1H, d, J=6.6Hz), 3.12-3.07 (4H, m), 2.71 (1H, d, J=13 Hz), 0.36 (3H, s).

[0153]17α-(2-Carbomethoxyethyl)-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17β-nitro-11β-[4-(N-piperidino)phenyl]estr-9-ene[A-1 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₂COOCH₃, R⁶═R¹²═H)]. To a mixtureof 12.0 g (23.0 mmol) of nitro intermediate A-1 (R¹=4-(N-piperidino)-,R⁶═R⁷═R¹²═H) in 65 mL of t-BuOH at room temperature was added 41.2 mL(460 mmol) of methyl acrylate, followed by the dropwise addition of 13.2mL (30.0 mmol) of 40% w/w Triton B in MeOH. After 1 h at roomtemperature, 132 mL of saturated aqueous NH₄Cl solution and 132 mL ofEtOAc were added. The aqueous layer was separated and extracted threetimes with 30 mL of EtOAc. The combined organic solutions were washedtwice with 132 mL of brine, dried over Na₂SO₄, filtered, and the solventwas removed under reduced pressure. Chromatography on silica gel (60%EtOAc in hexanes) afforded nitroester A-1 (R¹=4-(N-piperidino)-,R¹═—(CH₂)₂COOCH₃, R⁶═R¹²═H)11.8 g (85% yield). ¹H NMR (250 MHz, CDCl₃)δ7.04 (2H, d, J=8.6 Hz), 6.81 (2H, d, J=8.7 Hz), 4.35 (1H, s), 4.30 (1H,d, J=6.1 Hz), 4.03-3.93 (4H, m), 3.68 (3H, s), 3.11-3.07 (4H, m), 0.38(3H, s).

[0154]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-17β-(3-hydroxypropyl)-17β-nitro-11β-[4-(N-piperidino)phenyl]estr-9-ene[A-1 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)]. To a solution of8.13 g (13.3 mmol) of ester A-1 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₂COOCH₃,R⁶═R¹²═H) in 145 mL of THF at 0° C. was added 67.0 mL (67.0 mmol) of 1.0M DIBAL-H in hexanes. After 15 min, 55 mL of saturated aqueous potassiumsodium tartrate solution was added, thus causing a gel to form. Afterstirring the mixture at room temperature for 2 h, the gel haddissipated, giving a clear mixture. The aqueous layer was separated andextracted three times with EtOAc. The combined organic solutions werewashed twice with brine, dried over Na₂SO₄, filtered, and the solventwas removed under reduced pressure to afford nitropropanol A-1(R¹=4-(N-piperidino)-, R¹═—(CH₂)₃OH, R⁶═R¹²═H) as a yellow foam (7.83 g,100% yield). ¹H NMR (250 MHz, CDCl₃) δ7.05 (2H, d, J=8.6 Hz), 6.81 (2H,d, J=8.7 Hz), 4.38 (1H, s), 4.29 (1H, d, J=6.4 Hz), 4.02-3.93 (4H, m),3.68-3.50 (2H, m), 3.11-3.07 (4H, m), 2.90-2.75 (1H, m), 0.37 (3H, s).

[0155]17β-Amino-3,3-[1,2-ethanediylbis(oxy)]-5α-hydroxy-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)phenyl]estr-9-ene[A-4 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)]. To a solution of7.25 g (12.5 mmol) of nitropropanol A-1 (R¹=4-(N-piperidino)-,R⁷═—(CH₂)₃OH, R⁶═R¹²═H) and 13.4 g (250 mmol) of NH₄Cl in 70 mL of EtOH,70 mL of water, and 140 mL of THF at 70° C. was carefully added 49.0 g(749 mmol) of zinc dust (−325 mesh) over approximately 3 min. After theresulting mixture was stirred efficiently for 18 h, it was allowed tocool to room temperature then filtered through a pad of Celite with theaid of EtOAc. The filtrate was washed twice with brine, dried overNa₂SO₄, filtered, and the solvent was removed under reduced pressure toafford aminopropanol A-4 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)as a white amorphous solid (9.16 g), which was carried on to the nextstep without purification. ¹H NMR (250 MHz, CDCl₃) δ7.15 (2H, d, J=8.2Hz), 6.85 (2H, d, J=8.3 Hz), 4.40-4.20 (2H, m), 4.05-3.82 (4H, m), 3.46(2H, br s), 3.10 (4H, br s), 0.54 (3H, s).

[0156]17β-Amino-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)phenyl]estra-4,9-dien-3-one[A-6 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)]. To a vigorouslystirred milky-white mixture of 9.45 g (13.0 mmol assumed) of ketal A-4(R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H), 575 mL of CH₂Cl₂, and 12mL of water at 0° C. was added dropwise 16.6 mL (215 mmol) oftrifluoroacetic acid, which gradually caused a light blue colorationwhich faded to pale yellow over approximately 15 min. After stirringvigorously for 2 h, saturated aqueous NaHCO₃ was carefully added and themixture was allowed to gently stir at room temperature for 14 h. Themixture was extracted three times with EtOAc. The combined organicsolutions were washed twice with brine, dried over Na₂SO₄, filtered, andthe solvent was removed under reduced pressure to afford dienone A-6(R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H) as a yellow foam (6.18 g,74% adjusted yield over 3 steps) in a state of high purity by ¹H NMRanalysis. ¹H NMR (250 MHz, CDCl₃) δ7.04 (2H, d, J=8.6 Hz), 6.85 (2H, d,J=8.7 Hz), 5.76 (1H, s), 4.36 (1H, d, J=6.1 Hz), 3.62-3.42 (2H, m),3.13-3.09 (4H, m), 0.54 (3H, s). MS m/z (rel inten) 488 (M⁺, 21), 470(37), 387 (100), 320 (25), 162 (52), 96 (35).

EXAMPLE 7 Synthesis of17β-Hydroxylamino-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)phenyl]estra-4,9-dien-3-one[A-3 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)]

[0157]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-17β-hydroxylamino-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)phenyl]estr-9-ene[A-2 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)]. To a solution of4.34 g (7.47 mmol) of nitropropanol A-1 (R¹=4-(N-piperidino)-,R⁷═—(CH₂)₃OH, R⁶═R¹²═H) and 840 mg (15.7 mmol) of NH₄Cl in 49 mL ofEtOH, 49 mL of water, and 99 mL of THF at room temperature was added4.40 g (67.2 mmol) of zinc dust (−325 mesh). After stirring efficientlyfor 2.5 h, the mixture was filtered through a pad of Celite with the aidof EtOAc. The filtrate was washed twice with brine, dried over Na₂SO₄,filtered, and the solvent was removed under reduced pressure.Chromatography on silica gel (6% MeOH in EtOAc) afforded startingnitropropanol A-1 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H) (420mg, 10% recovery) and desired hydroxylamine propanol A-2(R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H) (2.95 g, 70% yield). ¹HNMR (250 MHz, CDCl₃) δ7.07 (2H, d, J=8.5 Hz), 6.82 (2H, d, J=8.7 Hz),5.29 (1H, br s), 4.35 (1H, s), 4.18-4.16 (1H, br s), 4.01-3.92 (4H, m),3.75-3.65 (1H, m), 3.60-3.51 (1H, m), 3.10-3.05 (4H, m), 1.04-0.93 (1H,m), 0.57 (3H, s).

[0158]17β-Hydroxylamino-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)phenyl]estra-4,9-dien-3-one(A-3 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)]. To a vigorouslystirred mixture of 2.95 g (5.20 mmol) of hydroxylamine A-2(R¹—=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H), 4.80 mL of water, and230 mL of CH₂Cl₂ at 0° C. was added dropwise 6.50 mL (84.2 mmol) oftrifluoroacetic acid. After stirring vigorously at 0° C. for 3 h, excesssaturated aqueous NaHCO₃ solution was carefully added. After stirring atroom temperature for 30 min, the mixture was extracted three times withEtOAc. The combined organic solution was washed twice with brine, driedover Na₂SO₄, filtered, and the solvent was removed under reducedpressure to afford a yellow foam (2.77 g). This material was combinedwith analogously prepared material (205 mg) in a minimal amount ofCH₂Cl₂ and chromatographed on silica gel (5.5% MeOH in EtOAc) to afforda yellow foam (1.99 g). This was combined with similar additionalmaterial (393 mg) in a minimal amount of CH₂Cl₂ and chromatographed onsilica gel (5.0% MeOH in EtOAc). Combination of the fractions determinedto be >97% pure by HPLC analysis afforded dienone A-3(R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H) (1.69 g, 52% adjustedyield). The majority of this material (1.68 g) was dried at 92° C. to94° C. in vacuo for 38 h to provide solvent-free product by ¹H NMRanalysis and of >97% purity by HPLC analysis. ¹H NMR (250 MHz, CDCl₃)δ7.03 (2H, d, J=8.6 Hz), 6.84 (2H, d, J=8.7 Hz), 5.75 (1H, s), 5.21 (1H,br s, exchangeable with D₂O), 4.28 (1H, d, J=6.0 Hz), 3.78-3.74 (1H, m),3.64-3.61 (1H, m), 3.10-3.02 (4H, m), 1.08-0.93 (1H, m), 0.64 (3H, s).MS m/z: LC-MS 505 (M+1); MS-MS 505 (M+1). Anal. Calcd. for C₃₂H₄₄N₂O₃:C, 76.15; H, 8.79; N, 5.55. Found: C, 75.90; H, 8.77; N, 5.50.

EXAMPLE 817β-(N-Formamido)-17α-[3-(formyloxy)propyl]-11β-[4-(N-piperidino)phenyl]estra-4,9-dien-3-one [A-8 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OCHO,R¹⁰═R⁶═R¹²═H)]

[0159] To a solution of 10.4 g (50.6 mmol) of dicyclohexylcarbodiimidein 28 mL of CHCl₃ at room temperature was added 101 mL (101 mmol) of1.00 M formic acid in CHCl₃, causing a white precipitate. After 5 min,the mixture was added to a solution of 6.18 g (12.7 mmol) of aminoalcohol A-6 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R⁶═R¹²═H)] and 12.4 mL(152 mmol) of pyridine in 55 mL of CHCl₃. After 15 min, a spatula tip of4-dimethylaminopyridine was added. After 2.5 h, another spatula tip of4-dimethylaminopyridine was added. An additional amount of a mixture of2.60 g (12.7 mmol) of dicyclohexylcarbodiimide and 25.3 mL (25.3 mmol)of 1.00 M formic acid in CHCl₃ in 10 mL of CHCl₃ was stirred for 5 min,then added to the reaction mixture. After 1 h, the reaction mixture wasdiluted with 600 mL of diethyl ether and stirred efficiently for 12 h,then filtered through a pad of Celite with the aid of diethyl etherrinsings. The filtrate was concentrated by rotary evaporation underreduced pressure then in vacuo. The residue was stirred with 100 mL ofEtOAc for 45 min, then the resulting solids were filtered through a padof Celite with the aid of EtOAc rinsings. The filtrate was combined witha smaller batch of the desired crude product (0.688 mmol, in theory)which had been prepared similarly up to this point. The solvent wasremoved under reduced pressure. The residue was iteratively dilutedthree times with 30 mL of toluene and concentrated under reducedpressure by rotary evaporation (to remove pyridine) giving 8.42 g of anorange/yellow foam. The material was chromatographed twice on silica gel(85% EtOAc in hexanes) to afford 4.66 g of an amorphous yellow solid. A1.63 g sample of this material was dried in vacuo for 21 h at 95° C.,affording a yellow amorphous solid (1.51 g, 51% adjusted yield). Theformate ester group was observed to be susceptible to slow cleavage inMeOH solution. Analysis by reverse phase analytical HPLC (C-18 column,YMC, inc.) showed >97% purity of the desired product, existing as twoequilibrating forms. Verification of such interconversion was obtainedby the separation of the individual forms by analytical HPLC, followedby their reinjection to provide virtually identical chromatograms. Thisbehavior was also observed by two-dimensional TLC experiments, as wellas in ¹H NMR spectra (ca. 2:1 ratio). ¹H NMR (250 MHz, CDCl₃ integrationadjusted for ratio of major and minor forms) δ8.03 (1H, s), 7.03 (2H, d,J=8.5 Hz), 6.83 (2H, d, J=8.6 Hz), 5.75 (1H, s), 5.32 (1H, s), 4.44-4.30(1H, m), 4.25-4.15 (2H, m), 3.10 (4H, br s), 0.50 (3H, s); minor form:8.14 (1H, d, J=12.4 Hz), 6.99 (2H, overlapping doublet), 5.95 (1H, d,J=12.4 Hz). Anal. Calcd. for C₃₄H₄₄N₂O₄: C, 74.97; H, 8.14; N, 5.14.Found: C, 74.72; H, 8.26; N, 5.07. MS m/z (rel inten) 544 (M⁺, 25), 320(23), 161 (100).

EXAMPLE 917β-(N-Formamido)-17α-(3-hydroxypropyl)-11β-[4-(N-piperidino)-phenyl]estra-4,9-dien-3-one[A-8 (R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R¹⁰═R⁶═R¹²═H)]

[0160] To a mixture of 1.43 g (2.62 mmol) of formate ester A-8(R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OCHO, R¹⁰═R⁶═R¹²═H)] and 24 mL of MeOHat room temperature with good stirring was added dropwise 0.48 mL ofconcentrated ammonium hydroxide, gradually causing the formation of ahomogeneous solution. After 1.2 h, 24 mL of saturated aqueous ammoniumchloride solution, 24 mL of water, and 24 mL of EtOAc were added. Theaqueous layer was separated and extracted three times with EtOAc. Thecombined organic solutions were washed twice with brine, dried overNa₂SO₄, filtered, and the solvent was removed under reduced pressure toafford 1.35 g (100% yield) of product. The material was combined with474 mg of analogously prepared crude product in a minimal amount ofCH₂Cl₂ and chromatographed on silica gel (8% MeOH in EtOAc) to afford ayellow foam (1.59 g). The material was iterative diluted three timeswith 15 mL of CH₂Cl₂ and concentrated under reduced pressure by rotaryevaporation to provide material free of all other solvents, by ¹H NMRanalysis. The material was dried at 95° C. for 23.5 h in vacuo to afford1.36 g of essentially solvent-free desired formamido propanol A-8(R¹=4-(N-piperidino)-, R⁷═—(CH₂)₃OH, R¹⁰═R⁶═R¹²═H) [1.45 g, 79% yield(adjusted for supplement)], in >97% purity by HPLC analysis.Equilibrating forms analogous to the above formamide A-8(R¹=4-(N-piperidino), R¹═—(CH₂)₃OCHO, R¹⁰═R⁶═R¹²═H) were similarlyobserved by analytical HPLC and ¹H NMR (ca. 1:1 ratio). ¹H NMR (250 MHz,CDCl₃ integration adjusted for ratio of forms) δ8.12 (1H, d, J=12.3 Hz),7.03 (2H, d, J=8.5 Hz), 6.83 (2H, d, 8.6 Hz), 6.39 (1H, d, J=12.9 Hz),5.75 (1H, s), 4.40-4.31 (1H, m), 3.65-3.62 (2H, m), 3.10-3.08 (4H, m),0.50 (3H, s); other form, partial: 8.01 (1H, s), 7.00 (2H, d, J=8.6 Hz),5.39 (1H, s), 0.49 (3H, s). Anal. Calcd. for C₃₃H,N₂O₃.0.25 H₂O: C,76.04; H, 8.61; N, 5.37. Found: C, 75.95; H, 8.62; N, 5.38. MS m/z (relinten) 516 (M+, 44), 387 (16), 320 (38), 161 (100).

EXAMPLE 10 Synthesis of5′-Oxo-11β-[4-(N-piperidino)phenyl]-spiro[estra-4,9-dien-17β,2′-pyrrolidino]-3-one[B-3 (R¹=4-(N-piperidino)-, R⁶═R¹²═H)]

[0161]3,3-[1,2-Ethanediylbis(oxy)]-5α-hydroxy-5′-oxo-11β-[4-(N-piperidino)phenyl]-spiro[estr-9-ene-17β,2′-pyrrolidine][B-2(R¹=4-(N-piperidino)-, R⁶═R¹²═H)]. A solution of the nitro ester B-1(R¹=4-(N-piperidino)-, R⁶═R¹²═H, R ═CH₃) (3.13 g, 5.10 mmol) wasprepared in 63 mL of 50% aqueous ethanol and 32 mL of THF. To this wasadded 1.93 g (73.4 mmol) of ammonium chloride and 20 g (306 mmol) ofzinc dust. The reaction mixture was heated at 70° C. for 20 h. Thereaction mixture was filtered through celite and the filtrateconcentrated. The crude product was chromatographed on silica geleluting with 6:3:1 ethyl acetate-hexane-methanol to give 1.97 g (70%yield) of pure B-2 (R¹=4-(N-piperidino)-, R⁶═R¹²═H): IR (solution,CDCl₃) 3495, 2995, 2855, 1685, 1506, 1438, 1384, 1226 cm⁻¹; ¹H NMR (250MHz, CDCl₃) δ7.03 (d, 2, J=8.5 Hz, ArH), 6.83 (d, 2, J=8.8 Hz, ArH),5.57 (s, 1, NH), 4.39 (s, 1, C₅ OH), 4.25 (d, 1, J=5.9 Hz, C_(11α)H),3.98-4.02 (m, 4, (OCH₂)₂), 3.09 (m, 4, N(CH₂)₂), 0.42 (s, 3, C₁₈ H).

[0162]5′-Oxo-11β-[4-(N-piperidino)phenyl]-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one.[B-3 (R¹=4-(N-piperidino)-, R⁶═R¹²═H)]. To a solution of 120 mg (0.23mmol) of B-2 (R¹=4-(N-piperidino)-, R⁶═R¹²═H) in 2.5 mL of CH₂Cl₂ wasadded 0.1 mL of water and the mixture was cooled to 0° C. To thesolution was added about 0.5 mL of trifluroacetic acid (TFA) dropwise.The reaction was stirred at 0° C. for 1 h. The reaction was quenchedwith saturated sodium bicarbonate solution, and extracted with CH₂Cl₂.The CH₂Cl₂ layer was washed with water, followed by brine and dried overanhydrous MgSO₄. The dried solution was then filtered and concentratedunder vacuum. The crude product was chromatographed on silica gel using5:5:1 methylene chloride-hexane-methanol as eluant to give 79 mg (76%yield) of pure B-3 (R¹=4-(N-piperidino)-, R⁶═R¹²═H). ¹H NMR (250 MHz,CDCl₃) δ6.99 (d, 2, J=8.7 Hz, ArH), 6.64 (d, 2, J=8.8 Hz, ArH), 5.79 (s,1, NH), 5.77 (s, 1, C₄ H), 4.36 (d, 1, J=6.4 Hz, C_(11α) H), 3.12 (m, 4,N(CH₂)₂), 0.49 (s, 3, C₁₈ H); mass spectrum, m/z (rel intensity)484(75), 374 (5), 320(16), 213(6), 174(17), 161(100); Anal. Calcd forC₃₂H₄₀N₂O₂: C, 79.30; H, 8.32; N, 5.78. Found: C, 79.12; H, 8.26; N,5.72.

EXAMPLE 11 Synthesis of11β-[4-(N,N-Dimethylamino)phenyl]-1′-hydroxy-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one[C-3 (R¹=4-(Me₂N—, R⁶═R¹²═H, R¹³═CH₃)]

[0163]1′,5α-Dihydroxy-11β-[4-(N,N-dimethylamino)phenyl]-3,3-[1,2-ethanediylbis(oxy)]-5′-methyl-spiro[estr-9-ene-17β,2′-pyrrolidine][C-2 (R¹=4-Me₂N—)—, R⁶═R¹²═H, R¹³═CH₃. To a stirred solution of C-1(R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═CH₃) (200 mg, 0.38 mmol) and (3.58 mmol) ofNaBH₃CN in 4 mL of methanol, was added 0.5 mL of AcOH. The reaction wasstirred at room temperature for 2 h. The reaction was quenched withsaturated NH₄Cl solution and extracted with CH₂Cl₂. The organic layerwas washed with water, followed by brine and dried over anhydrousNa₂SO₄. The organic layer was filtered and concentrated to give crudeC-2 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═CH₃) which was used without furtherpurification in the next step. ¹H NMR (250 MHz, CDCl₃) δ7.06 (d, 2,J=8.7 Hz, ArH), 6.64 (d, 2, J=8.7 Hz, ArH), 4.35 (s, 1, C, OH), 4.19 (d,1, J=6.2 Hz, C_(11α)H), 3.98-4.02 (m, 4, (OCH₂)₂), 2.88 (s, 6, N(CH₃)₂),1.19 (d, 3, J=6.5 Hz, HONCHCH₃), 0.62 (s, 3, C₁₈ H).

[0164]11β-[4-(N,N-Dimethylamino)phenyl]-1′-hydroxy-5′-methyl-spirofestra-4,9-dien-17β,2′-pyyrrolidine]-3-one[C-3 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═CH₃)]. To a solution of 200 mg (0.38mmol) of C-2 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═CH₃) in 2.0 mL of CH₂Cl₂, wasadded 0.1 mL of water and the mixture was cooled to 0° C. To the cooledsolution was added about 0.5 mL of TFA dropwise. The reaction wasstirred at 0° C. for 1 h. The reaction was then quenched with saturatedsodium bicarbonate solution, and extracted with CH₂Cl₂. The CH₂Cl₂ layerwas washed with water, followed by brine and dried over anhydrousNa₂SO₄. The dried solution was filtered and concentrated under vacuum.The crude product was chromatographed on silica gel using 3:1 ethylacetate-hexane as eluant to give 114 mg (65% yield) of pure C-3(R¹=4-MeN—, R⁶═R¹²═H, R¹³═CH₃). ¹H NMR (250 MHz, CDCl₃) δ7.02 (d, 2,J=8.6 Hz, ArH), 6.65 (d, 2, J=8.7 Hz, ArH), 5.74 (s, 1, C₄ H), 4.30 (d,1, J=6.8 Hz, C_(11α)H), 2.89 (s, 6, N(CH₃)₂), 1.19 (d, 3, J=6.4 Hz,HONCHCH₃), 0.69 (s, 3, C₁₈ CH₃); mass spectrum, m/z (rel intensity)459(8), 458(23), 442(31), 280(12), 134(100), 121(33), 96(7); Anal.Calcd. for C₃₀H₄₀N₂O₂.0.25 H₂O: C, 77.45; H, 8.83; N, 5.61. Found: C,77.46; H, 8.78; N, 6.02.

EXAMPLE 12 Synthesis of11β-[4-(N,N-Dimethylamino)phenyl]-1′-hydroxy-spiro[estra4,9-dien-17β,2′-pyrrolidine]-3-one[C-3 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═H)]

[0165]1′,5α-Dihydroxy-11β-[4-N,N-dimethylamino)phenyl]-3,3-[1,2-ethanediylbis(oxy)]-spiro[estr-9-ene-17β,2′-pyrrolidine][C-2(R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═H)]. To a stirred solution of C-1(R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═H) (200 mg, 0.39 mmol) and 234 mg (3.77 mmol)of NaBH₃CN in 5 mL of methanol was added 0.5 mL of AcOH. After stirringat room temperature for 2 h, the reaction was quenched with saturatedNH₄Cl solution and extracted with CH₂Cl₂. The organic layer was washedwith water, followed by brine and dried over anhydrous Na₂SO₄. Theorganic layer was filtered and concentrated to give the crude productwhich was used without further purification in the next step. ¹H NMR(250 MHz, CDCl₃) δ7.04 (d, 2, J=8.7 Hz, ArH), 6.64 (d, 2, J=8.8 Hz,ArH), 4.37 (s, 1,C₅ OH), 4.16 (d, 1, J=7.4 Hz, C_(11α)H), 3.92-4.02 (m,4, (OCH₂)₂), 2.90 (s, 6, N(CH₃)₂), 0.64 (s, 3, C₁₈H).

[0166]11β-[4-N,N-Dimethylamino)phenyl]-1′-hydroxy-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one[C-3 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═H)]. To a solution of 200 mg (0.39 mmol)of C-2 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═H) in 5.0 mL of CH₂Cl₂ was added 0.1mL of water and the mixture was cooled to 0° C. To the cooled solutionwas added about 0.5 mL of TFA dropwise. After stirring for 1 h at 0° C.,the reaction was quenched with saturated sodium bicarbonate solution,and extracted with CH₂Cl₂. The CH₂Cl₂ layer was washed with water,followed by brine and dried over anhydrous Na₂SO₄. The dried solutionwas filtered and concentrated under vacuum. The crude product waschromatographed on silica gel using 3:1 ethyl acetate-hexane as eluantto give 115 mg (65% yield) of pure C-3 (R¹=4-Me₂N—, R⁶═R¹²═H, R¹³═H). ¹HNMR (250 MHz, CDCl₃) δ7.00 (d, 2, J=8.7 Hz, ArH), 6.65 (d, 2, J=8.8 Hz,ArH), 5.75 (s, 1, C₄ H), 4.29 (d, 1, J=6.7 Hz, C_(11α)H), 2.91 (s, 6,N(CH₃)₂), 0.66 (s, 3, C₁₈ H); mass spectrum, m/z (rel intensity)446(11), 428(66), 347(82), 280(27), 226(31), 134(80), 121(87), 96(100),83(42); Anal. Calcd for C₂₉H₃₈N₂O₂.0.25 H₂O: C, 77.44; H, 8.84; N, 5.84.Found: C, 77.20; H, 8.60; N, 6.21.

[0167] The biological activity of the compounds of this invention wasexamined by means of in vitro and in vivo tests.

[0168] Receptor Binding:

[0169] The affinity of the compounds for the human progesterone hormonereceptor was determined by standard procedures similar to those thathave been described in Horwitz, et al., Cell, 28: 633-42 (1982) andMockus, et al., Endocrinology, 110: 1564-71 (1982). The receptor wasobtained in cytosol from human T-47D breast cells and [³H]-R5020 wasused as the radioligand. T47D cells (1 billion/ml) were homogenized inTEDG buffer (10 mM Tris, 1.5 mM EDTA, 1 mM dithiothreitol, 1 mM sodiummolybdate, and 10% glycerol) using a Dounce pestle A, and the homogenatewas centrifuged at 34,000×g for 1 hour. The supernatant was stored at−80° C. An aliquot of receptor preparation was combined with testcompound, 0.4 nM [³H]-R5020, and TEDG buffer to a final volume of 150 μLand incubated for 4 hours at 4° C. in microtiter plates. At the end ofincubation 40 μL 40% polyethylene glycol and 15 μL 1% human gammaglobulin was added to the incubate and the contents of each well wereharvested onto double thick B filter mats (Wallac LKB) using a TomTecharvester. A film of Meltilux scintillant wax was applied to the driedfilter mats and the mats were counted in a scintillation counter todetermine inhibition of [³H]-R5020 binding. Data are expressed as IC₅₀values, i.e., the concentration of compound that inhibits radioligandbinding by 50%.

[0170] Table 1 shows that compounds of the present invention bindstrongly to the progestin receptor but with varying degrees of affinity.

[0171] Animal tests were also performed to further characterize thebiological activity of the compounds of the invention.

[0172] Determination of progestational and antiprogestational activityin vivo:

[0173] Progestational activity and antiprogestational activity weredetermined in rabbits by means of the McGinty test (test compound alone,procedure of McGinty et al., Endocrinology, 24: 829-832 (1939)) oranti-McGinty test (test compound plus progesterone, procedure of Tamaraet al., Jpn. J. Fertil. Steril. 24: 48-81 (1979)). Results were scoredaccording to McPhail (McPhail, J. Physiol., 83: 146 (1934)). These arestandard procedures well-known to those skilled in the art. The resultsof these assays are shown in Tables 2 (agonist activity) and 3(antagonist activity). Most of the compounds shown exhibitedantiprogestational activity. Some compounds were extremely potent inthis regard. For example, compounds I (R¹=4-Me₂N—C₆H₄, X═O, R⁶═R⁸═R¹²═H,R⁷═CH₃CC, R⁹═CHO) and I ((R¹=4-Me₂N—C₆H₄, X═O, R⁶═R⁸═R¹²═H, R⁷═CH₃CC,R⁹═OH) were completely effective in blocking the action of progesteroneat a dose of only 0.3 μg in the anti-McGinty assay (Table 3). Howeverthe latter compound also exhibited some progestational (agonist)activity at a high doses in the McGinty assay (Table 2) and at thehighest dose in the anti-McGinty assay. Thus a variety of agonist andantagonist properties may be found among compounds of this invention.

[0174] Anti-estrogenic Activity:

[0175] Certain of the compounds exhibited non-competitiveanti-estrogenic activity of the type reported for mifepristone, forexample by Wolf et al. (Fertil. Steril. 52: 1055-1060 (1989).Surprisingly they exhibited this activity in spite of the fact that theydo not have the 17β-hydroxyl substituent characteristic of bothmifepristone and estrogens such as estradiol but instead have17β-nitrogen substituents. Thus, when immature female rabbits wereadministered11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(1-propynyl)estra-4,9-dien-3-oneorally at 10 mg/day concurrently with 5 μg of estradiol per day and theuteri were removed and weighed, the uterine weight, which was raisedfrom 216.7±37.2 (S.E.) mg with no estradiol to 1337±105 mg withestradiol alone, was reduced to 716±96.6 mg. TABLE 1 Receptor BindingAffinity Relative Binding Affinity hPR Structure R¹ R² X R⁶ R⁷ R⁸ R⁹ R¹³R¹⁴ IC₅₀(nM) Progesterone 3.3 I 4-Me₂N H O H —CC—CH₃ H OH — — 14.3 I4-Me₂N H O H —CC—CH₃ CH₃ OH — — 7.1 I 4-Me₂N H O H —CC—CH₃ H H — — 8.3 I4-Me₂N H O H —CC—CH₃ H CH₃C(═O) — — 1.3 I 4-Me₂N H O H —CC—CH₃ H HC(═O)— — 0.7 II 4-Me₂N H O H — H OH CH₃ H 5.2 II 4-Me₂N H O H — H OH H H 3.5

[0176] TABLE 2 Progestational Activity McGinty Assay Dose (Micrograms)(Agonist) 0.3 3 30 Structure R¹ R¹² X R⁶ R⁷ R⁸ R⁹ R¹³ R¹⁴ McPhail IndexVehicle 0 Progesterone 2.45 ± 0.14 I 4-Me₂N H O H —CC—CH₃ H OH — — 0 ± 00 ± 0 0.7 ± 0.0 I 4-Me₂N H O H —CC—CH₃ CH₃ OH — — 0 ± 0 0 ± 0 0 ± 0 I4-Me₂N H O H —CC—CH₃ H H — — 0 ± 0 0 ± 0 0 ± 0 I 4-Me₂N H O H —CC—CH₃ HCH₃C(═O) — — 0 ± 0 0 ± 0 0 ± 0 I 4-Me₂N H O H —CC—CH₃ H HC(═O) — — 0 ± 00 ± 0 0 ± 0 II 4-Me₂N H O H — H OH CH₃ H 0 ± 0 0 ± 0 0 ± 0 II 4-Me₂N H OH — H OH H H 0 ± 0 0 ± 0 0 ± 0

[0177] TABLE 3 Antiprogestational Activity Anti-McGinty Dose(Micrograms) Assay (Antagonist) 0.3 3 30 Structure R¹ R¹² X R⁶ R⁷ R⁸ R⁹R¹³ R¹⁴ McPhail Index Vehicle 0 RJW 1719 2.45 ± 0.14 I 4-Me₂N H O H—CC—CH₃ H OH — — 0 ± 0 0 ± 0 2.5 ± 0.4 I 4-Me₂N H O H —CC—CH₃ CH₃ OH — —2.0 ± 0.2 0 ± 0 0 ± 0 I 4-Me₂N H O H —CC—CH₃ H H — — 1.6 ± 0.3 0.2 ± 0.10 ± 0 I 4-Me₂N H O H —CC—CH₃ H CH₃C(═O) — — 1.8 ± 0.3 0.1 ± 0.1 0 ± 0 I4-Me₂N H O H —CC—CH₃ H HC(═O) — — 0 ± 0 0 ± 0 0 ± 0 II 4-Me₂N H O H — HOH CH₃ H 2.1 ± 0.3 2.4 ± 0.4 0.7 ± 0.4 II 4-Me₂N H O H — H OH H H 2.7 ±0.0 2.3 ± 0.5 0.07 ± 0.07

[0178] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed as new and desired to be secured by Letters Patent ofthe United States is:
 1. A hormonal or antihormonal steroid compound ofstructure I,

wherein R¹ is (R² R³ N(O)_(r)), where r is 0 or 1 and R² and R³ are eachindependently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, any of which may be optionally substituted; or

where q is 0 or 1, Y is —(CH₂)_(m) where m is an integer of 0 to 5, or Yis —(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is aninteger of 0 to 2, and Z is a heteroatom (optionally substituted) andwhere any of the CH₂ groups may be optionally substituted; or R¹ isN-imidazolyl,- N-pyrrolyl-, H, halo-, HO—, CF₃SO₂O—, C₁₋₆ alkyl-O—, C₁₋₆alkyl-S—, C₁₋₆ alkyl-S(O)—, C, alkyl-S(O₂)—, C₁₋₆ alkyl-CO—, C₁₋₆alkyl-CH(OH)—, NC—, HCC—, C₆H₅CC—, 2′-furyl, 3′-furyl, 2′-thiophenyl,3′-thiophenyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl, 2′-thiazolyl,2′-N-methylimidazolyl, 5′-pyrimidinyl, C₆H₅—, H₂C═CH—, C₁₋₆ alkyl, orMeC(═CH₂)—; R¹² is H or halo; or R¹ and R¹² combine to form a ring

where W is CH₂, CH, NH, N, O, or S, and R⁴ is H or C₁₋₆ alkyl; X is O orNOR⁵, where R⁵ is H or C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₂ aryl, or heteroaryl, any of which may be optionallysubstituted; or X is (H, H), (H, OH), (H, OSi(C₁₋₆ alkyl)₃), or (H,OCOR⁵), where R⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,heteroaralkyl, heteroaralkenyl or heteroaralkynyl , any of which may beoptionally substituted; or

where Y is —(CH₂)_(m)— where m is an integer of 0 to 3, or Y is—(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is an integerof 0 to 2 and Z is a heteroatom (optionally substituted) or Z is acarbon atom substituted with one or two C₁₋₆ alkyl groups; R⁶ is H, C₁₋₆alkyl or halogen; R⁷ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may beoptionally substituted, CN, COOR¹⁰ or CONHR¹⁰, where R¹⁰ is H, C₁₋₁₈alkyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₂ aryl,aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl, any of which may be optionallysubstituted; s is 0 or 1; R⁸ and R⁹ are each independently H, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, R¹⁰CO, OR¹¹, any of which may beoptionally substituted, where R¹⁰ is H, C₁₋₁₈alkyl, C₂₋₁₈alkenyl, C₂₋₁₈alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl,heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl any ofwhich may be optionally substituted, and where R¹¹ is H, C₁₋₆ alkyl,Si(C₁₋₆ alkyl)₃, 2′-tetrahydropyranyl or R¹⁰ CO where R¹⁰ is as definedabove; and wherein when s is 0, R⁸ may also be O⁻ and R⁹ is ═CH₂ or═C(H, C₁₋₆), ═C(H, aryl) or ═C(C₁₋₆)₂ and the nitrogen attached to the17-position is positively charged; and pharmaceutically acceptable saltsthereof.
 2. A hormonal or antihormonal steroid compound of structure II,

wherein R¹ is (R² R³ N(O)_(r))—, where r is 0 or 1 and R² and R³ areeach independently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, any of which may be optionally substituted; or

where q is 0 or 1, Y is —(CH₂)_(m)— where m is an integer of 0 to 5, orY is —(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is aninteger of 0 to 2, and Z is a heteroatom (optionally substituted) andwhere any of the CH₂ groups may be optionally substituted; or R¹ isN-imidazolyl,- N-pyrrolyl-, halo-, HO—, CF₃SO₂O—, C₁₋₆ alkyl-O—, C₁₋₆alkyl-S—, C₁₋₆ alkyl-S(O)—, C₁₋₆ alkyl-S(O₂)—, C₁₋₆ alkyl-CO—, C₁₋₆alkyl-CH(OH)—, NC—, HCC—, C₆H₅CC—, 2′-furyl, 3′-furyl, 2′-thiophenyl,3′-thiophenyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl, 2′-thiazolyl,2′-N-methylimidazolyl, 5′-pyrimidinyl, C₆H₅—, H₂C═CH—, C₁₋₆alkyl, orMeC(═CH₂)—; R¹² is H or halo; or R¹ and R¹² combine to form a ring

where W is CH₂, CH, NH, N, O, or S, and R⁴ is H or C₁₋₆ alkyl; X is O orNOR⁵, where R⁵ is H or C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₂ aryl, or heteroaryl, any of which may be optionallysubstituted; or X is (H, H), (H, OH), (H, OSi(C₁₋₆ alkyl)₃), or (H,OCOR⁵), where R⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may beoptionally substituted; or

where Y is —(CH₂)_(m)— where m is an integer of 0 to 3, or Y is—(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is an integerof 0 to 2 and Z is a heteroatom (optionally substituted) or Z is acarbon atom substituted with one or two C₁₋₆ alkyl groups; R⁶ is H, C₁₋₆alkyl or halogen; s is 0 or 1; R⁹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, R¹⁰CO, OR¹¹, any of which may be optionally substituted, whereR¹⁰is H, C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl,C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl any of which may be optionallysubstituted, and where R¹¹ is H, C₁₋₆ alkyl, Si(C₁₋₆ alkyl)₃,2′-tetrahydropyranyl or R¹⁰CO where R¹⁰ is as defined above; R¹³ and R¹⁴are each independently H, C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl or aralkynyl,heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any ofwhich may be optionally substituted; or R¹³R¹⁴ is O, and R¹⁵ and R¹⁶ areeach H or combine to form a group ═CH₂, optionally substituted, andpharmaceutically acceptable salts thereof.
 3. The steroid havingstructure I of claim 1 wherein R¹—Ph is 4-aminophenyl,4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl,4-(N-piperidino)phenyl, 4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl,1-methylindol-5-yl or 1-m or ethyl-2,3-dihydroindol-5-yl or R¹—Ph is theN-oxide of 4-(N,N-dimethyl)phenyl, 4-(N-piperidino)phenyl,4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl; X is O, NOH, or NOCH₃;R⁶ is H, CH₃, F or Cl; R⁷ is H, methyl, ethynyl, 1-propynyl, 3-propynyl,3-hydroxypropyl, 3-hydroxy-1-propenyl (E- or Z-),3,3,3-trifluropropyn-1-yl, 3-hydroxypropyn-1-yl, (CH₂)₂COOCH₃,(CH₂)₂COOC₂H₅, (CH₂)₂COCH₃, CC—C₆H₅, CH₂C₆H₅, CN, or COOCH₃; R¹ is H,CH₃, or CH₂C₆H₅; and R⁹ is H, OH, OCH₃, CHO, CH₃CO, C₆H₅CO or C₆H₅CH₂CO.4. The steroid of claim 2, wherein R¹—Ph is 4-aminophenyl,4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl,4-(N-piperidino)phenyl, 4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl,1-methylindol-5-yl or 1-methyl-2,3-dihydroindol-5-yl; X is O, NOH, orNOCH₃; R⁶is H, CH₃, F or Cl; R⁹ is H, OH, CHO, CH₃CO, C₆H₅CO orC₆H₅CH₂CO; R¹³ and R¹⁴ are O, (H, H), (H, CH₃) or (CH₃, CH₃); and R¹⁵and R¹⁶ are (H, H) or R¹⁵ R¹⁶ is (═CH₂).
 5. The steroid of claim 1selected from the group consisting of:11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxylamino)-17α-(1-propynyl)-estra-4,9-dien-3-one,11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxylamino)-17α-(1-propynyl)-estra-4,9-dien-3-one,11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estra-4,9-dien-3-one,11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(1-propynyl)estra-4,9-dien-3-one,17β-amino-11β-(4-(N,N-dimethylamino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one,17β-amino-11β-(4-(N-piperidino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one,17β-(N-acetamido)-11β-(4-(N,N-dimethylamino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one,17β-(N-acetamido)-11β-(4-(N-piperidino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one,11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(1-propynyl)estra-4,9-dien-3-oneand its N-oxide,17β-(N-formamido)-11β-(4-(N-piperidino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-oneand its N-oxide,11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxylamino)-17α-(3-hydroxypropyl)-estra-4,9-dien-3-one,11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxylamino)-17α-(3-hydroxypropyl)-estra-4,9-dien-3-one,11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one,11β-(4-(N-piperidino)phenyl)-17β-(N-hydroxy-N-methylamino)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one,17β-amino-11β-(4-(N,N-dimethylamino)phenyl)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one,17β-amino-17α-(3-hydroxypropyl)-11β-(4-(N-piperidino)phenyl)estra-4,9-dien-3-one,17β-(N-acetamido)-11β-(4-(N,N-dimethylamino)phenyl)-17α-(3-hydroxypropyl)estra-4,9-dien-3-one,17β-(N-acetamido)-17α-(3-hydroxypropyl)-11β-(4-(N-piperidino)phenyl)estra-4,9-dien-3-one,11-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(3-hydroxypropyl)estra-4,9-dien-3-oneand17β-(N-formamido)-17α-(3-hydroxypropyl)-11β-(4-(N-piperidino)phenyl)estra-4,9-dien-3-one,11β-(4-(N,N-dimethylamino)phenyl)-17β-(N-formamido)-17α-(3-formyloxy-1-propyl)estra-4,9-dien-3-oneand17β-(N-formamido)-17α-(3-formyloxy-1-propyl)-11β-(4-(N-piperidino)phenylestra-4,9-dien-3-one.
 6. The steroid of claim 2, selected from the groupconsisting of11β-(4-(N,N-dimethylamino)phenyl)-1′-hydroxy-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N-piperidino)phenyl)-1′-hydroxy-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N,N-dimethylamino)phenyl)-1′-hydroxy-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N-piperidino)phenyl)-1′-hydroxy-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N,N-dimethylamino)phenyl)-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N-piperidino)phenyl)-5′-methyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N,N-dimethylamino)phenyl)-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N-piperidino)phenyl)-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N,N-dimethylamino)phenyl)-5′-oxo-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N-piperidino)phenyl)-5′-oxo-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one,11β-(4-(N,N-dimethylamino)phenyl)-1′-formyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-oneand11β-(4-(N-piperidino)phenyl)-1′-formyl-spiro[estra-4,9-dien-17β,2′-pyrrolidine]-3-one.7. A method of therapeutically treating the activity of progesteronecomprising administering a therapeutically effective amount of thecompound of claim 1, to a patient in need thereof for a therapeuticpurpose.
 8. The method of claim 7, wherein said therapeutic purpose isthe treatment of endometriosis or uterine fibroids.
 9. The method ofclaim 7, wherein said therapeutic purpose is cervical ripeningpreparatory to labor and delivery of offspring.
 10. The method of claim7, wherein said therapeutic purpose is the control or regulation offertility.
 11. The method of claim 7, wherein said therapeutic purposeis the treatment of tumors or cancers.
 12. The method of claim 7,wherein said therapeutic purpose is hormone replacement therapy.
 13. Amethod of therapeutically treating the activity of progesteronecomprising administering a therapeutically effective amount of thecompound of claim 2, to a patient in need thereof for a therapeuticpurpose.
 14. A method of preparing the compound of claim 1, comprising:i) treating a compound of structure (III) by reduction of the nitrogroup, followed by hydrolysis of X and elimination of the hydroxyl group

wherein R¹ is (R² R³ N(O)_(r))—, where r is 0 or 1 and R² and R³ areeach independently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, any of which may be optionally substituted; or R¹ is

where q is 0 or 1, Y is —(CH₂)_(m)— where m is an integer of 0 to 5, orY is —(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is aninteger of 0 to 2, and Z is a heteroatom (optionally substituted) andwhere any of the CH₂ groups may be optionally substituted; or R¹ isN-imidazolyl-N-pyrrolyl-, H, halo-, HO—, CF₃SO₂O—, C₁₋₆ alkyl-O—,C₁₋₆alkyl-S—, C₁₋₆ alkyl-S(O)—, C₁₋₆ alkyl-S(O₂)—, C₁₋₆ alkyl-CO—, C₁₋₆alkyl-CH(OH)—, NC—, HCC—, C₆H₅CC—, 2′-furyl, 3′-furyl, 2′-thiophenyl,3′-thiophenyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl, 2′-thiazolyl,2′-N-methylimidazolyl, 5′-pyrimidinyl, C₆H₅—, H₂C═CH—, C₁₋₆ alkyl, orMeC(═CH₂)—; R¹² is H or halo; or R¹ and R¹² combine to form a ring

where W is CH₂, CH, NH, N, O, or S, and R⁴ is H or C₁₋₆ alkyl; X is

where Y is —(CH₂)_(m)— where m is an integer of 0 to 3, or Y is—(CH₂)_(n)—Z—(CH₂)_(p)— where n is an integer of 0 to 2, p is an integerof 0 to 2 and Z is a heteroatom (optionally substituted) or Z is acarbon atom substituted with one or two C₁₋₆ alkyl groups; R⁶ is H, C₁₋₆alkyl or halogen; R⁷ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₂ aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl,heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may beoptionally substituted, CN, COOR¹⁰or CONHR¹⁰, where R¹⁰ is H, C₁₋₁₈alkyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₂ aryl,aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl,heteroaralkenyl or heteroaralkynyl, any of which may be optionallysubstituted.
 15. A method of therapeutically treating the activity ofprogesterone comprising administering a therapeutically effective amountof the compound of claim 2, to a patient in need thereof for atherapeutic purpose.
 16. The method of claim 7, further comprisingadministering one or more pharmacologically active compounds.
 17. Themethod of claim 15, further comprising administering one or morepharmacologically active compounds.